Confidential: For Review Only · The genetics of isolated colonic Crohn’s disease place it approximately midway between Crohn’s disease with small intestinal involvement and ulcerative

Confidential: For Review O

nly

Recent advances in clinical practice: a systematic review of

isolated colonic Crohn’s disease- the third inflammatory

bowel disease?

Journal: Gut

Manuscript ID gutjnl-2016-312673.R2

Article Type: Recent advances in clinical practice

Date Submitted by the Author: 05-Sep-2016

Complete List of Authors: Subramanian, Sreedhar; Royal Liverpool University Hospital,

Gastroenterology Ekbom, Anders; Karolinska Institutet, Dep of Medicine Solna, Clinical Epidemiology Unit Rhodes, Jonathan M; UNIVERSITY OF LIVERPOOL

Keywords: CROHN'S COLITIS

https://mc.manuscriptcentral.com/gut

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Recent advances in clinical practice: a systematic review of isolated colonic Crohn’s

disease – the third inflammatory bowel disease?

5355 words

Sreedhar Subramanian (1), Anders Ekbom (2), Jonathan M Rhodes (1).

1. Institute of Translational Medicine, University of Liverpool,The Henry Wellcome Laboratory,Nuffield Building,Crown St.,LiverpoolL69 3GE, UK 2. Department of Medicine, Karolinska Institute, Solna 171 76, Stockholm, Sweden

Corresponding author: Jonathan M Rhodes [email protected]

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ABSTRACT

The genetics of isolated colonic Crohn’s disease place it approximately midway between Crohn’s disease with small intestinal involvement and ulcerative colitis, making a case for considering it as a separate condition. We have therefore systematically reviewed its epidemiology, pathophysiology, and treatment. Key findings include a higher incidence in females (65%) and older average age at presentation than Crohn’s disease at other sites, a mucosa-associated microbiota between that found in ileal Crohn’s disease and ulcerative colitis, no response to mesalazine, but possibly better response to anti-TNF than Crohn’s disease at other sites. Diagnostic distinction from ulcerative colitis is often difficult and also needs to exclude other conditions including ischaemic colitis, segmental colitis associated with diverticular disease and tuberculosis. Future studies, particularly clinical trials, but also historical cohorts, should assess isolated colonic Crohn’s disease separately. INTRODUCTION

Diagnosis of Crohn’s disease is often contentious when ileal involvement is lacking. This has a long history. Colitis with skip lesions and rectal sparing was considered in 19301 as “regional migratory ulcerative colitis”. Crohn’s classic 1932 paper did not include cases with colonic involvement2 although non-tuberculous granulomatous involvement of ileum and colon had been reported in 19233 and later by others.4, 5 From the 1930’s to the 1950’s, colitis without rectal or terminal ileal involvement was usually designated “regional” or “segmental” colitis.6 The British surgeon Wells first used “Crohn’s disease of the colon” when describing cases of granulomatous regional colitis in 1952.7 Initially this was not widely accepted and Kirsner (1960) continued to refer to cases with submucosal granulomata and skip lesions as ulcerative colitis.8 Identification of Crohn’s disease of the colon separately from ulcerative colitis was strongly reinforced by Lockhart-Mummery and Morson, (1960) who described 25 cases with features including non-bloody diarrhoea, anal fistulae, rectal sparing, skip lesions and strictures.9 Histopathology showed submucosal giant cell granulomata, fibrous thickening, and regional lymph node enlargement. This paper caused a “paradigm shift” that has led practice since. It was reinforced the following year when Cornes and Stecher reported 45 patients with isolated colonic Crohn’s disease, with fistulation in nearly two thirds, and skip lesions in 20% .10 Later evidence that colonic Crohn’s disease, unlike ulcerative colitis, might be improved by faecal diversion,11, 12 treatable by segmental resection13, and associated with poor outcomes after ileal pouch-anal anastomosis,14 seemed to confirm even more securely its position as a form of Crohn’s disease and distinct from ulcerative colitis. Distinction of colonic Crohn’s disease from ulcerative colitis may be difficult though. The term “indeterminate colitis” was introduced to describe cases, “10-20%”, where, after colectomy and examination of the resected colon, a clear diagnosis is not possible.15 The term was often incorrectly applied to patients without colectomy until “inflammatory bowel disease unclassified” (IBD-U) was recommended for such cases.16

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The scene is now changing again – extensive data show that isolated colonic Crohn’s disease is genetically separable from Crohn’s disease involving the small intestine.17 When the ratio of Crohn’s-associated genes to ulcerative colitis-associated is compared with disease phenotype isolated colonic Crohn’s disease lies approximately midway between ileal Crohn’s and ulcerative colitis. IBD-U, although statistically separable from ulcerative colitis overlaps it considerably and ileo-colonic Crohn’s disease similarly overlaps ileal Crohn’s disease (Figure 1). This finding led to recommendation that Crohn’s disease with ileal involvement (ileal and ileocolonic), isolated colonic Crohn’s disease and ulcerative colitis should be considered as three separate conditions. It is therefore timely to review the epidemiology, genetics, serology, microbiology, and response to treatment of isolated colonic Crohn’s disease and to reconsider whether this “evidence” favours isolated colonic Crohn’s disease as a variant of Crohn’s disease, as a variant of ulcerative colitis, or as a separate condition. METHODS

The medical literature was searched using National Library of Medicine/Pubmed to 1st December 2015 using the terms “colonic and Crohn’s” “Crohn’s and colitis” “epidemiology and Crohn’s”. We conducted additional searches for “smoking and Crohn’s disease” and “oral contraception and Crohn’s”. Later (to 1st June 2016) additional searches for “Crohn’s” and each of the therapies covered were performed. After removal of duplicates and screening of abstracts for relevance, 840 were selected for further review (Supplementary Figures 1 &2). Whilst the literature search was fully systematic, the subject of this review is necessarily much broader than that of a conventional systematic review. We have only included full publications in english language and have not attempted to judge quality of the data. For epidemiological studies we included all reports that (a) contained data on at least 100 patients with Crohn’s disease and (b) included separate data for isolated colonic Crohn’s disease (Montreal classification L2). Where published studies had overlapping patient base and time period we used only the more completely described data set to avoid duplication. For other aspects of the review (genetics, serological testing, response to therapies and association with environmental factors) we included all studies that identified isolated colonic Crohn’s disease separately. For therapeutic studies we have separately identified data that have been obtained from randomized clinical trials and those that have been obtained from cohort studies. It should be noted that, whereas pure ileal Crohn’s and pure colonic Crohn’s should be readily distinguished by a comprehensive diagnostic assessment including ileal intubation, incomplete assessment could mislabel ileocolonic as colonic. This should be taken into account particularly in respect of older studies but we have taken care to ensure that all data included here regarding isolated colonic disease relate to patients thought at the time of publication not to have ileal disease. Statistical analysis was performed using StatsDirect3 v 3.0.171 StatsDirect Ltd, UK. PATHOLOGY, DIFFERENTIAL DIAGNOSIS, AND DISEASE COURSE – DEFINING THE

CONDITION

The histological features of isolated colonic Crohn’s disease were first defined by Lockhart-Mummery and Morson.9 They labeled patients with this diagnosis because “they had the same characteristic pathology in the large intestinal lesions as that described by Hadfield18 for the disease as it affects the small intestine”. Gross appearances of the colon following

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colectomy include less sharp demarcation of ulceration than typically seen in ulcerative colitis and with areas of intact intervening mucosa. In some cases, very marked fibrous thickening with associated stricturing was present. Fibrosis and oedema sometimes extended into the pericolic fat and enlargement of regional lymph nodes was marked. Warren later split the macroscopic features into three patterns: isolated rectal disease; stricturing colonic disease; diffuse colitis – usually with rectal sparing, and noted that approximately 75% develop perianal pathology during their disease course.19 Microscopic features described by Morson included discontinuous inflammation and ulceration which could extend into the submucosa or deeper into the wall as the basis of fistula formation, plus focal crypt irregularity. Non-caseating epithelioid granulomas were present in the majority, distributed through all layers of the bowel wall as well as regional lymph nodes. Other features included submucosal lymphangiectasia and neuromatous hyperplasia.20 It has subsequently been noted that the earliest lesions – aphthous ulcers – which usually overlie lymphoid follicles, are preceded by a “red ring” sign on colonoscopy, biopsy of which reveals a lymphoid follicle surrounded by reactive hypervascularisation.21 Histopathology alone is diagnostic only in the minority – in a series of 103 cases of Crohn’s colitis, diagnosis was determined by microscopy alone in 28%, by distribution (rectal sparing and/or discontinuity) alone in 22% and by combination of the two in 50%.22 Particularly discriminatory features suggesting Crohn’s colitis rather than ulcerative colitis include granulomata, submucosal inflammation, and relative preservation of goblet cells.23,24 At an international workshop expert pathologists “correctly” identified only 64% of cases with Crohn’s colitis and 74% with ulcerative colitis25 leading the European consensus on histopathology of inflammatory bowel disease (2013) to note that “accurate discrimination between the two diseases (Crohn’s colitis and ulcerative colitis) is not yet optimal amongst expert gastrointestinal pathologists”. Given that inflammatory disease pathogenesis is multifactorial an alternative interpretation would be that there is a continuous phenotypic spectrum that runs through from “typical” ulcerative colitis, through IBD-unclassified to “typical” Crohn’s colitis. Early studies reported an additional incidence peak of Crohn’s disease in the elderly resulting from cases particularly affecting the sigmoid colon.26 Following the later clarification of segmental colitis associated with diverticular disease (SCAD) this seems probably attributable to SCAD. SCAD can be indistinguishable histologically from inflammatory bowel disease and includes a “Crohn’s-like” variant with granulomata.27 This reflects emphasis often placed on the diagnostic specificity of the granuloma. However, granulomas are only found in colonoscopic biopsies at diagnosis in about 66% of adults with colonic Crohn’s disease, falling to 18% at follow-up.28 Moreover granulomas, particularly in association with crypts, can be found in ulcerative colitis.29 Other forms of colitis that may need to be considered in the differential include ischemic colitis (see earlier) and infections including amoebiasis and tuberculosis but it is beyond the scope of this review to consider these further. Localisation of disease to the colon remains fairly constant over time. The largest published data set by far is the 16,902 Crohn’s disease cohort, including 2,933 with isolated colonic disease, in the recent genotype/phenotype association study.17 This confirmed previous

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reports of low rates of progression to ileo-colonic disease (5-14% over 7-10 years). 30-32 Although luminal narrowing is common, stricturing (B2 disease) as defined in the Vienna/Montreal classifications requires the presence of prestenotic dilatation or obstructive signs or symptoms and this very rarely occurs, eg 0/45 cases in a Belgian series 33 whereas penetrating disease (B3) as defined by the Vienna classification (ie including peri-anal fistulae) occurred in 23% in the same series, less frequently than in patients with ileal disease (46%; P=0.0003) or ileocolonic (28.6%; NS). The much larger genotype/phenotype association study confirmed that cumulative probability of progression to B2 and B3 combined over ten years was substantially lower in colonic disease – 23%, than in ileocolonic disease - 62%, or ileal disease - 68%.17 The risk of surgery (discussed later) was also much lower at ten years (22%) than for ileo-colonic (42%) or ileal disease (62%). A recent meta-analysis showed that colon cancer risk in isolated colonic Crohn’s disease is similar to ulcerative colitis of equivalent extent with a pooled standardized incidence ratio (SIR) of 1.7; 0.9-2.6 95%CI (population based data) compared with SIR 1.8; 1.2-2.4 for ulcerative colitis but rising to SIR 18.2; 7.8-35.8 for extensive colonic Crohn’s disease in a referral centre population compared with SIR 21.6; 15.0-31.0 for extensive ulcerative colitis.34

EPIDEMIOLOGY

Changes over time

Studies reporting sequential data from a single centre or region show interesting time trends. Studies from UK35,36 and Sweden37 reported a marked increase in isolated colonic Crohn’s as a proportion of total Crohn’s from 1970 to 1990 (Figure 2A) whereas later studies, particularly from France38 have shown a downward trend since 1990. When looked at across all geographical areas, (Table 1), although there is no obvious difference in proportion of isolated colonic disease between countries or regions, there is a similar time trend with increase in isolated colonic disease between 1960 and 1990, peaking at an average of about one third of all Crohn’s disease cases, and decreasing since (p=0.02 by polynomial regression, Figure 2B).

Sex variation

We found eight studies which stated the sex distribution of patients with isolated colonic Crohn’s disease. In all but one the female preponderance was equal or greater to that reported from the same study for total Crohn’s disease (Table 1) – isolated colonic Crohn’s disease averaging 65.1% female, compared with Crohn’s disease excluding isolated colonic 55.3% female (P=0.027 by paired t test). Age at diagnosis

Age at diagnosis of isolated colonic Crohn’s disease (in seven studies; Table 1), has a median between 28 and 45, around 10 years older than generally reported for all Crohn’s – eg median 25 years in the 16,902 patients studied by Cleynen et al17. Older age of isolated colonic versus other sites of Crohn’s disease was also confirmed by the IBDchip European Project.85 The preponderance of isolated colonic disease amongst children with very early onset Crohn’s disease is discussed later. Smoking

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Cigarette smoking is associated with increased risk for development and progression of Crohn’s disease but reduced risk for ulcerative colitis. Smoking is more strongly associated with risk for ileal and ileo-colonic Crohn’s disease than for isolated colonic disease (Table 2). Only one study (of nine)79 reported a higher rate of smoking amongst patients with isolated colonic Crohn’s disease. If the South African data84 which reported exceptionally high rates (73%) across all groups are excluded, the other studies report rates for smoking amongst patients with isolated colonic disease that averaged 37.8% compared with 49.8% (P=0.008 by paired t test) for other Crohn’s disease sites. This smoking rate is probably slightly higher than for the general population – approximately 30% European adults were smokers in 2008 (WHO).86 Smoking worsens prognosis of Crohn’s disease overall and cessation of smoking improves it.87,88 This has been studied less in isolated colonic disease but the conclusion is similar. The largest study80 included 688 patients with Crohn’s colitis, 978 with ulcerative colitis and 118 with “indeterminate” colitis. Sixty-one per cent of patients with ulcerative colitis or indeterminate colitis had stopped smoking before disease onset compared with only 12% in isolated colonic Crohn’s disease. In women but not men with isolated colonic disease the risk of needing immunosuppression was increased amongst smokers (10-yr cumulative risk 48% in non-smokers vs 58% in smokers, P<0.01). An earlier study74 showed that smokers with Crohn’s colitis relapsed approximately 50% more often (P=0.028) and with more pain (P<0.007) than non-smokers. Thus smoking at best has a neutral effect on isolated colonic Crohn’s disease but more likely is harmful. Oral contraception

Meta-analysis of 14 studies, with adjustment for smoking, showed a relative risk of 1.51 (95%CI 1.17-1.96, P=0.002) for Crohn’s disease amongst women currently taking oral contraception89. The relative risk for ulcerative colitis was also increased at 1.53 (1.21-1.94, P=0.001). Six of the seven studies that reported risk associated with oral contraception separately for isolated colonic disease found a significant association (Table 3) with relatively high odds ratio (2.63), risk ratios (3.6 and 3.23) or hazard ratio (4.13). The sole exception91 only included 8 cases with isolated colonic Crohn’s disease and showed no overall association between oral contraception and risk for Crohn’s disease. Excluding the latter study91, five of the other six show higher risks amongst oral contraceptive users for isolated colonic Crohn’s than for other sites.

Oestrogen-associated ischaemic colitis as a confounder

An early study from Birmingham50 reported patients with apparent oral contraceptive-associated colonic Crohn’s disease who had non-granulomatous colitis with rectal sparing. Ischaemic colitis is a rare but recognized complication of oral contraception that might cause diagnostic confusion. 97,98,99 Most cases have a short duration with typical features of ischaemic colitis including abdominal pain, and rectal bleeding. Colonoscopy shows mucosal friability but no linear ulceration and the proximal colon and rectum are typically normal. Such cases should be readily distinguishable from colonic Crohn’s disease but Tedesco100

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reported five cases of oral contraceptive-associated colitis with features that overlapped more with colonic Crohn’s disease than ischaemic colitis. Moreover, colonic “thumbprinting”, a characteristic feature of ischaemic colitis, has been reported in Crohn’s disease.101 It is unclear whether diagnostic overlap with milder cases of oral contraceptive-associated ischaemic colitis contributes to the female preponderance of isolated colonic Crohn’s disease. If it does then the change to lower oestrogen dosing in later versions of the contraceptive pill might be a plausible explanation for the apparent fall off in cases in recent decades.102 Clinicians should be aware of the possible associations between oral contraception and inflammatory bowel disease or ischaemic colitis and advise patients accordingly – such advice should usually include at least a temporary cessation of oral contraception to assess impact on the colitis.

GENETICS

The strongest genetic association with IBD is the link between NOD2/CARD15 and Crohn’s disease. Meta-analysis of 42 studies showed that this association was stronger for Crohn’s disease with small bowel involvement than for those without (OR 2.53; 95%CI 2.01-3.16).103

Subsequent study of 1528 patients with Crohn’s disease from 8 centres (in 7 European countries) (IBDchip) confirmed the association of NOD2/CARD15 with ileal involvement and also showed that Interleukin23 receptor polymorphisms were more strongly associated with isolated colonic Crohn’s (OR 2.20; 95%CI 1.17-4.57).85 The most consistent genetic link with ulcerative colitis is with the rare Major histocompatibility Complex (MHC) / Human Leucocyte Antigen (HLA) Class II allele HLA-DRB*0103. This occurs in less than 2% in European and white North American populations and is absent in the Japanese. It is strongly associated with colonic Crohn’s disease where it is present at up to 32% frequency with Odds Ratios for isolated colonic disease of 5.1-18.5 compared with Crohn’s disease at other sites.104 The largest study to compare genetic associations with Crohn’s disease phenotype included 19713 patients from 49 centres across 16 countries in Europe, North American and Australasia.17 This confirmed that the strongest association with isolated colonic Crohn’s disease was HLA-DRB1*01:03 (p=1.47 x 10-23, ileal vs colonic OR 0.32, 95%CI 0.29-0.41; ileocolonic vs colonic OR 0.47, 95%CI 0.39-0.57). The only other loci that were significant across all analyses in this study were NOD2 (16q12), again associated with increased risk for ileal involvement (OR ileocolonic vs colonic 1.61,1.59, and 1.89 for the three NOD2 polymorphisms tested) and also MST1 (macrophage stimulating -1 that encodes a protein which induces macrophage phagocytosis) polymorphisms which were more weakly associated with ileal involvement (OR 1.07 -1.10 according to polymorphism and whether comparing ileal or ileocolonic with colonic disease). When overall genetic risk scores for Crohn’s disease and ulcerative colitis were computed as a ratio and compared with phenotype, isolated colonic Crohn’s disease was found to be approximately “balanced” in respect of Crohn’s disease versus ulcerative colitis genetic risk factors (Figure 1). It was found though that even the combination of smoking status with the strongest genetic predictors could only explain 6.8% of the variance for disease location. ISOLATED COLONIC CROHN’S DISEASE IN CHILDHOOD AND SINGLE GENE DISORDERS

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Amongst children with very early onset Crohn’s disease there is a marked preponderance of cases with isolated colonic disease eg 76.5% before age 5105 and 42% before age 8.106 Amongst younger cases there is a strong male preponderance – eg 1.6:1 across all Crohn’s disease presenting <5105 and some of this is accounted for by X-linked single gene disorders. The first such condition to be identified was X-linked Chronic Granulomatous Disease. Chronic Granulomatous Disease is associated with defects in neutrophil function leading to skin lesions and in around 40% with a form of inflammatory bowel disease that is indistinguishable from Crohn’s disease, typically with predominant colorectal and perianal involvement .107 It is due to mutations in one of four NADPH oxidase complex component genes of which the commonest (CYBB) located on the X chromosome accounts for about 65% cases. Rapid developments in DNA sequencing have allowed identification of over 50 further single gene disorders that present as inflammatory bowel disease, typically as colonic disease and with presentation before age 6, defined as Very Early Onset IBD or VEO-IBD.108 VEO-IBD cases account for 4-10% of paediatric inflammatory bowel disease.109 One of the commoner single gene variants is in the coding region of X-linked inhibitor of apoptosis protein (XIAP) that accounts for about 4% of male patients with paediatric onset Crohn’s disease.110

SEROLOGY INCLUDING ANTI-MICROBIAL AND ANTI-NEUTROPHIL ANTIBODIES

Anti-microbial antibodies such as Anti-Saccharomyces cerevesiae (ASCA) and antibodies to outer membrane protein (ompC) are found less often and/or at lower titre in isolated colonic Crohn’s than in other Crohn’s phenotypes.111 Meta-analyses confirm this particularly for ASCA.112-114 Average sensitivity of ASCA for isolated colonic Crohn’s disease diagnosis is 31% but with a wide range (8-59%) and an average 14% positivity rate in ulcerative colitis (Table 4). The clinical utility of ompC antibodies has been less studied but reported positivity/sensitivity in isolated colonic Crohn’s disease is substantially lower than that for ASCA. Anti-neutrophil antibodies, particularly an atypical peri-nuclear antibody (pANCA), are present in around 55% of patients with ulcerative colitis114 and 23% of patients with isolated colonic Crohn’s disease (Table 4). This compares with pANCA positivity of around 11% in Crohn’s disease overall and 3% in non-IBD controls.114 A combination of positive ASCA and negative pANCA is more discriminatory eg positivity rate in isolated colonic Crohn’s disease of 52% compared with 9% in ulcerative colitis122 but is still insufficiently predictive for routine clinical use.125 Thus the frequency in isolated colonic Crohn’s disease of both ASCA and pANCA antibodies lies somewhere in between that found in Crohn’s disease with ileal involvement (more likely ASCA+, and pANCA-) and that found in ulcerative colitis (more likely ASCA- and pANCA+).

MICROBIOTA

The faecal microbiota in active inflammatory bowel disease is commonly dysbiotic with reduced bacterial diversity.126,127 This could be secondary to inflammation yet still significant

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in maintaining chronicity. The large study of pre-treatment Crohn’s disease by Gevers showed only a mild dysbiosis in the faecal microbiota and much greater separation of Crohn’s disease from healthy controls when the mucosa-associated microbiota was studied.128 Ileal and rectal mucosal samples typically showed a reduction in Firmicutes such as Faecalibacterium prausnitzii and an increase in Proteobacteria such as Escherichia coli as well as in Veillonella, Haemophilus and Fusibacteria. This confirmed many previous studies showing an increase in mucosa-associated E. coli in Crohn’s disease as well as several showing a reduction in F. prausnitzii

129-132. The faecal and mucosa-associated microbiota in isolated colonic Crohn’s disease are generally closer to that of healthy controls than is found in patients with ileal or ileocolonic Crohn’s disease (Table 5). Thus Baumgart et al

129 found that an increase in ileal mucosa-associated E. coli and reduction in ileal F. prausnitzii was only present in patients with Crohn’s disease who had ileal involvement and not in those with isolated colonic disease. Similarly, a study of twins with/without Crohn’s disease showed that faecal microbial diversity was only reduced and Proteobacteria increased in patients with ileal involvement and not in patients with isolated colonic disease.130 A previous report by the same group also showed a reduction in F. prausnitzii in Crohn’s patients with ileal involvement but not in isolated colonic disease.131 Both the twin study by Willing131 and the large study in children128 and adolescents134 did however show differences between the mucosa-associated microbiota in isolated colonic Crohn’s disease and ulcerative colitis. 16sRNA pyrosequencing of mucosal samples133 confirms the increase in E. coli and reduced F.

prausnitzii in Crohn’s disease with ileal involvement with milder changes in isolated colonic disease, although the latter did show some reduction in F. prausnitzii compared with healthy controls. This study also confirmed that the mucosa-associated microbiota are consistent at different sites from ileum to rectum in the same individual. In conclusion, mucosa–associated microbiota changes in Crohn’s disease are more marked than faecal changes. The microbiota in isolated colonic Crohn’s disease, show changes that tend to be less marked and less consistent than those found in Crohn’s disease with ileal involvement.

RESPONSE TO TREATMENT

Mesalazine

Systematic reviews show no convincing benefit of oral mesalazine (5-aminosalicyclic acid) over placebo either in induction of remission or in maintenance of medically induced remission in Crohn’s disease as a whole1345138 although they may have a modest benefit in maintaining surgically-induced remission.139 Sulphasalazine (sulphapyridine linked via azo bond to 5-aminosalicylate) has possible modest efficacy in induction of remission.134, 136 Amongst trials that have reported data separately for isolated colonic Crohn’s disease, only one trial studied the effect of oral mesalazine in remission induction140 and four studied its effect in maintenance of medically-induced remission141-144 (Table 6). In none of these was

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mesalazine significantly more effective than placebo but in two studies141,142 there was a weak signal suggesting a better response in ileal disease. A single trial of olsalazine showed worse results than for placebo, probably because of drug-related diarrhea.145 Sulphasalazine was no better than placebo in two trials of maintenance146,147 but there was a weak signal of efficacy in remission induction in two trials147,148 but these only studied 17 and 27 patients with isolated colonic disease respectively (including placebo). Apart from case reports there have been no published studies of rectal mesalazine in isolated colonic Crohn’s disease. It can be reasonably concluded that mesalazine and olsalazine do not have efficacy in isolated colonic Crohn’s disease. Sulphasalazine possibly has some efficacy in remission induction. Antibiotics

Systematic reviews suggest a beneficial effect for antibiotics in the induction of remission for Crohn’s disease though these have included diverse antibiotics and small trials.149-151 The largest study to date is for rifaximin.152 Three doses were tested: 400, 800, 1200mg or placebo twice daily for 12 weeks with good efficacy overall but no dose response. Amongst patients with isolated colonic disease higher remission rates (51%) were found for rifaximin (pooled doses) than for placebo (37%) and efficacy was better in this group than for other disease sites (Table 7). Metronidazole has also shown better efficacy in isolated colonic Crohn’s disease but based on very small numbers (Blichfeldt153: n=6 crossover; Sutherland154: 8 active and 4 placebo). In a study of 134 patients randomly assigned to ciprofloxacin and metronidazole, both 500mg twice daily, or placebo in combination with budesonide 9mg daily155 a trend was seen towards benefit in patients with colonic involvement compared with those without but separate data were not reported for patients with isolated colonic disease. A large randomized trial of long duration (up to 2 years) antibiotic therapy (clarithromycin, rifabutin and clofazimine) targeted against Mycobacterium avium paratuberculosis in patients also receiving tapered prednisolone showed short term efficacy with 66% active in remission at 16 weeks compared with 50% placebo (P=0.02) and 39% relapsed by 12 months compared with 56% placebo (P=0.054).156 No differential response was seen according to disease location but data were not presented separately for patients with isolated colonic disease.

Rifaximin and metronidazole thus show some evidence of efficacy in patient with isolated colonic Crohn’s disease and antibiotics tend to perform better in this group of patients than in Crohn’s disease at other sites but based on very small data sets. Further trials are clearly needed.

Corticosteroids

Given the widespread use of corticosteroids in Crohn’s disease the quality of evidence for their efficacy is surprisingly poor. There have only been two placebo-controlled trials of standard glucocorticosteroids.147,148 Each of these included only 8 steroid-treated patients with isolated colonic disease (Table 8) with one trial147showing no benefit and the other148showing efficacy. There has never been a trial to assess dose-responsiveness to

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conventional corticosteroids in Crohn’s disease so optimal dosage is unknown. More data are available for budesonide but trials have focused predominantly on patients with ileal or ileo-colonic disease so data in isolated colonic disease are again very sparse. The data from one comparison with mesalazine157, support efficacy in isolated colonic Crohn’s disease, possibly with a weaker effect than conventional corticosteroids158, but reduced corticosteroid side-effects.

Anti-TNF

None of the randomised trials of infliximab159,160 or adalimumab161-164 reported subgroup analyses of outcomes based on disease location. In a randomised, placebo controlled trial of certolizumab pegol, patients with colonic (OR 2.39, 95% CI 0.99-5.75, P=0.052) and ileocolonic disease (OR 2.07, 95% CI 1.01-4.28, P=0.048) were more likely to achieve remission at week 6 compared to ileal disease (OR 0.42, 95% CI=0.18-0.99, P=0.048)165(Table 9) Several cohort studies have assessed colonic disease location as a predictor of response to anti-TNF agents, four with infliximab and one with adalimumab. Three cohort studies assessing induction therapy with infliximab166-168 all showed better response rates in isolated colonic disease than for disease at other sites. Paradoxically, cohort studies of infliximab maintenance in children169 and of adalimumab maintenance in adults170 both showed higher risk of lost response or dose escalation in isolated colonic disease. Overall, the evidence supports good efficacy for anti-TNF therapy in induction of remission in isolated colonic Crohn’s disease but possibly with a higher subsequent rate of loss of response.

Vedolizumab

In the combined induction and maintenance study of vedolizumab there was no significant difference in efficacy in isolated colonic disease compared with other locations.171 (Table 9)

Enteral nutrition

Exclusive enteral nutrition is effective as primary therapy in patients with active Crohn’s disease172,173 and partial enteral nutrition has shown efficacy in maintenance of remission.174 In ulcerative colitis total parenteral nutrition and bowel rest are ineffective175 and comparison of enteral with parenteral nutrition showed no difference in efficacy176 implying no efficacy for enteral nutrition either. Whether enteral nutrition is effective as primary therapy in isolated colonic Crohn’s disease is controversial. Relatively few studies provide separate data on patients with isolated colonic Crohn’s disease (Table 10). Five of the six studies are in children. Two studies178,179 report poorer results in children with isolated colonic disease compared with those with small intestinal involvement. Numbers are small though (19 cases of isolated colonic disease across the two trials) and the other studies (including 72 cases of isolated colonic disease across four trials) found no significant difference in remission rates for those with isolated colonic disease compared with other

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sites. Further trials of exclusive enteral nutrition are needed in patients with isolated colonic disease.

Surgery

Faecal diversion

Colonic Crohn’s disease commonly responds to “bowel rest” induced by a defunctioning ileostomy whereas ulcerative colitis does not.11, 12 Instillation of unfiltered ileostomy contents into the defunctioned colon induced relapse whereas instillation of content that had passed through a 0.22micron pore diameter filter did not, implying a role for bacteria in pathogenesis.183 Defunctioning ileostomy has become less commonly performed for the treatment of uncomplicated colonic Crohn’s disease since it was shown that at least 50% relapsed after continuity was restored.184

Resection

The cumulative risk of surgery for isolated colonic Crohn’s disease is reported as 22-33% by 10 years after diagnosis compared with around 75-90% for ileal disease.17,67 Partial resection, either right hemicolectomy for proximal disease or a segmental resection for more distal disease has been shown to be successful therapy for colonic Crohn’s disease185,

186 as is colectomy with ileo-rectal anastomosis for more extensive disease if the rectum is uninvolved187,188. Approximately 75% of patients with ileo-rectal anastomosis will still have a functioning anastomosis after 10 years and about two thirds of those treated by segmental resection will not have required a further resection.188 Recurrence rates are similar after either procedure.189 This contrasts with left-sided ulcerative colitis, where the tempting option of left hemicolectomy with right-sided colo-anal anastomosis consistently fails, usually with rapid recurrence of colitis in the retained colon.190 It should be noted though that segmental resection for colon cancer complicating colonic Crohn’s disease has been associated with high (39%) risk for metachronous colon cancer191 suggesting that panproctocolectomy might be a safer option for such patients.

Ileo-anal pouch reconstruction

Crohn’s disease has generally been considered a contra-indication for restorative ileo-anal pouch surgery and even in selected patients pouch failure of 57% has been reported from the UK.192 Others have suggested that it may be successful in very carefully selected patients. Thus, a series of 3,707 patients with ileal-pouch anal anastomosis from the Cleveland Clinic included 150 with Crohn’s disease, of whom 32 had a pre-operative diagnosis, the remainder diagnosed by post-operative histopathology or on follow-up. Amongst 59 patients with Crohn’s disease reaching 10 year follow-up, pouch survival was 80%.193 Forty nine of 132 patients (37%) needing pouch excision had a histological diagnosis of Crohn’s disease. Considering that a pre-operative diagnosis of Crohn’s disease was only present in less than 1% of patients receiving pouch-anal anastomosis these data do not make a strong case for this procedure in patients with a definite diagnosis of colonic Crohn’s disease.

CONCLUSION

Current data suggest that the genetics, microbiota, serology and smoking association of isolated colonic Crohn’s disease lie between those of ileo/ileocolonic Crohn’s disease and

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ulcerative colitis and make a strong case for this phenotype being considered separately (Table 11). Genetic data in particular show good separation from ileal/ileocolonic Crohn’s disease and the low rate of progression from isolated colonic to ileo-colonic disease help to justify this distinction. There is a disappointing paucity of good quality therapeutic data but the lack of response to mesalazine, whose target cell is the surface epithelium, suggests a different pathophysiology to ulcerative colitis and there are important differences from ulcerative colitis in surgical outcomes, including a good response to segmental resection in selected cases and a generally poor response to pouch reconstruction. Taken together this implies a compelling need for isolated colonic Crohn’s disease to be identified separately from ileal/ileocolonic disease and from ulcerative colitis. This is particularly important when future therapeutic trials are designed and when cohort studies are reported. Acknowledgements: Funding: None Conflicts of interest: SS has received speaker fee from MSD, Actavis, Abbvie, Dr Falk pharmaceuticals, Shire and received educational grant from MSD, Abbvie, Actavis and is an advisory board member for Abbvie, Dr Falk pharmaceutics, Janssen and Vifor pharmaceuticals. JMR is or has been a member of advisory boards for Atlantic, Pharmacosmos, Procter and Gamble, Vifor and Falk, has received speaking honoraria from Abbott, Falk, Ferring, Glaxo Smith Kline, Merck, Procter and Gamble, Schering Plough, Shire, and Wyeth, and with the University of Liverpool and Provexis UK, holds a patent for use of a soluble fibre preparation as maintenance therapy for Crohn’s disease plus a patent pending for its use in antibiotic-associated diarrhoea. Provenance and peer review: Commissioned; externally peer reviewed.

LEGENDS TO FIGURES:

1. Comparison between Crohn’s disease genetic risk score and ulcerative colitis genetic risk score for different locations of Crohn’s disease, ulcerative colitis and IBD unclassified (from Cleynen et al,17 with permission. This shows that isolated colonic Crohn’s lies approximately equidistant genetically between ileal Crohn’s disease and ulcerative colitis.

2A. Isolated colonic Crohn’s as percentage of all Crohn’s disease by year in studies reporting sequential data from the same centres or geographical areas. 2B. Isolated colonic Crohn’s disease as percentage of all Crohn’s disease by year in all studies. Supplementary Files 1. PRISMA flow diagram. 2. PRISMA checklist.

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158. Bar-Meir S, Chowers Y, Lavy A, et al., Budesonide versus prednisone in the treatment of active Crohn's disease. The Israeli Budesonide Study Group. Gastroenterology 1998;115:835-40.

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164. Colombel JF, Sandborn WJ, Rutgeerts P, et al. Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial. Gastroenterology 2007; 132: 52–65.

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177. Lochs H, Steinhardt HJ, Klaus-Wentz B, et al.Comparison of enteral nutrition and drug treatment in active Crohn's disease. Results of the European Cooperative Crohn's Disease Study. IV. Gastroenterology 1991;101:881-8.

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Authors/ref Country Years analysed

Number of cases all CD

All CD % female

Isolated colonic CD as % of total CD

Isolated colonic CD % female

CD excluding Isolated colonic % female (calculated)

Median Age at presentation (colonic CD)

unspecified or indeterminate as ratio to colonic CD in same series

Cornes10 UK 1961 131 46 34 60 38 41-50 -

Gollop39 USA 1943-82

103 64 36 68 62 25-34 -

Loftus40 USA 1940-93

225 54 32 - - - -

Humphreys41 UK 1966-81

440 58 40 - - - -

Ekbom42 Sweden 1965-83

1469 53 25 - - 33 (mean) -

Kyle35 UK 1955-88

856 63 41 63 63 40-49 -

“ “ “ “ 1964-69

122 - 30 - - - -

“ “ “ “ 1970-75

167 - 40 - - - -

“ “ “ “ 1976-81

204 - 46 - - - -

“ “ “ “ 1982-87

263 - 54 - - - -

Lapidus37 Sweden 1955-59

83 61 14 - - - -

1960-64

145 48 15 - - - -

1965-69

270 51 21 - - - -

1970-74

364 53 26 - - - -

1975-79

331 54 26 - - - -

1980-84

348 58 32 - - - -

1985-89

395 49 32 - - - -

Gunesh36 UK (Cardiff)

1950-60

40 - 13 - - - -

“ “ “ “ 1960-70

89 - 17 - - - -

“ “ “ “ 1970-80

148 - 34 - - - -

“ “ “ “ 1980-90

217 - 38 - - - -

Yapp43 UK (Cardiff) 1991-95

84 68 43 - - - -

Gunesh36 “ “ 1996-2005

212 61 43 68 55 - -

Jayanthi44 UK 1972-89

235 50 25 (incr from

1972 to 89)

- - - -

Cottone45 Italy 1975-95

882 - 18 - - - -

Jacobsen46 Denmark 1978-87

196 67 (1978-

87)

32 - - - -

“ “ “ “ 1988-97

354 “ “ 42 - - - -

“ “ “ “ 1998-2002

230 “ “ 51 - - - -

Wright47 S.Africa 1980-84

134 69 27 - - - 0.44

Manninen48 Finland 1986-99

470 50 40% 1986 31% 1999

- - - 0.56

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Economou49 Greece 1983-2005

105 37 40 - - - 0.40

Rhodes50 UK 1984 395 55 22 72 50 28 (subset)

-

Gower-Rousseau51

France 1994 674 57 19 - - 28 1.15

Auvin52 France 1988-99

367 (< 17y)

47 10 - - - 0.54

Spanish53 Spain 1997 635 52 17 - - - -

Jess54 Denmark 1962-87

374 58 30 - - - -

“ “ “ “ 1991-93

58 66 43 - - - -

“ “ “ “ 2003-04

209 54 37 - - - -

Chow55 China 1987-2005

109 29 35 - - - -

Chouraki38 France 1988-2007

7409 56 11 - - - 0.90

“ “ “ “ 1988-90

544 - 23 - - - -

“ “ “ “ 1997-99

1044 - 13 - - - -

“ “ “ “ 2006-07

533 - 5 - - - -

Romberg-Camps56

Netherlands 1991-2003

476 61 27 66 59 34 (mean) 0.63

Bjornsson57 Iceland 1995-2009

279 54 55 - - - 0.08

Tozun58 Turkey 2001-03

216 44 26 - - - -

Lakatos59 Hungary 2002-06

163 48 36 -

Nguyen60 USA/Canada 2003-05

579 - 19 - - - 0.30

Ott61 Germany 2004-06

168 55 18 - - - 0.43

Siddique62 Kuwait 2005-6 206 52 14 - - - -

Chen63 USA 2005-10

628 55 21 50 56 - -

Lucendo64 Spain 2000-12

599 49 24 - - - 0.10

Henckaerts65 Belg 2007 874 - 17 - - - 0.03

Herrinton66 USA 2008 948 55 40 - - - 0.10

Hancock67 UK 2008 675 62 20 (“enriched”)

74 59 31 (mean) -

Aloi68 Italy 2009-13

10 (<5y)

- 50 - - - -

“ “ “ “ “ “ 215 (6-18y)

- 15 - - - 1.00

Aljebreen69 Saudi 2009-13

497 41 8 - - - -

Burisch70 Western europe

2010 345 48 26 - - - 1.19

“” “” Eastern europe

2010 99 41 20 - - - 0.30

Eglinton71 NZ 2011 507 63 42 - - - -

Ng72 Asia-pacific 2011-12

166 Asia 39% Austr 52%

24 - - - 0.53

Cleynen17 16 countries 2015 16,902 56 24 - - - 0.06

Table 1. Studies of Crohn’s disease age and sex distribution and proportion of total, where isolated colonic Crohn’s disease separately identified (in approximate median date order).

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• “current smoking” variably either smoking at time of diagnosis or at time of sampling but excluding “ex-smoking”

Table 2. Studies of smoking in Crohn’s disease where isolated colonic disease separately identified

Author/ref Year Country Number of cases CD

Nature of study Current smoking OR/RR for CD phenotype

Current smoking * isolated

colonic CD %

Current smoking all

CD%

Current smoking

CD excluding isolated

colonic %

Current smoking healthy

controls %

Current smoking

UC %

Somerville73 1984 UK 82 Case control RR for smoking and CD: Small bowel only 3.5 (0.8-

14.6) Colon only 4.7 (1.4-16.1) Small and large bowel 4.5

(1.8-11.5)

- 56 - 26 -

Holdstock74 1984 UK 150 Consecutive outpatients

- 25 (smokers

with isolated colon CD had more relapses P=0.028)

35 52 - 8

Tobin75 1987 UK 137 Case control RR for smoking at onset and CD:

Small bowel only 1.4 (0.5-4.0)

Ileum and asc colon 6.0 (2.1-17.2)

Small bowel and rest of colon 3.9 (1.5-10.2)

Colon only 2.5 (0.8-7.3)

- 47 - 33 (controls for UC 40%)

11

Lindberg76 1992 Sweden 231 Postal questionnaire

(95% response)

- 42 51 53 - -

Breuer-Katschinski77

1995 Germany 346 Postal questionnaire

(82% response)

- 49 50 49 - -

Russel78 1998 Europe (20

centres, 13

countries)

457 Prospective consecutive

cases

- 35 47 59 - 16

Cosnes79 1999 France 622 Consecutive outpatients

- 54 49 49 - -

Cosnes80 2004 France 688 all colonic

Consecutive outpatients

- 61 - - 42

Aldhous81 2007 UK (Scotland)

408 Retrospective outpatients

- 33 43 50 - -

Hancock67 2008 UK 675 Database OR 1.64 (1.09-2.45) for never smokers with isolated

colonic CD vs ileal or ileocolonic

51 (ever)

61 (ever)

63 - -

Chen82 2011 USA 628 University database

OR 1.69 (1.07-2.66) for any ileal involvement (L1+L3)

vs colon only (L2)

25 37 38 - -

Nunes83 2013 Spain 3224 National registry

- 26 34 35 - -

Chivese84 2015 S. Africa 194 Prospective consecutive

cases

RR 3.63 (1.32-9.98) for ileo-colonic vs colonic;

RR 3.54 (1.06-11.83) for ileal vs colonic

62 73 79 - -

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Author/Ref Study design N (total CD) n/% isolated colonic CD taking

OC at onset

n/% all other CD taking OC at

onset

OR/RR (95%CI) for OC use compared

with healthy controls (when documented by

disease location)

OC use in isolated

colonic vs all other CD

Rhodes50 Case control matched for

age and year of onset

37 9/12 75% 11/25 44% - NS Increased P=0.09

Vessey90 Cohort study in patients

attending family planning clinics

18 4/7 57% 4/11 36% - NS increased 0.63

Lashner91 Case control 51 (incl 8 isolated colonic)

- - Isolated colonic OR0.50(0.05–5.26)

Small bowel only 1.25 (0.34–4.64)

Ileocolonic

0.56(0.20-1.52)

NS reduced (and no

significant association in

this study between OC use and any

Crohns)

Sandler92 Case control Age matched and excluding onset before

menarche

184 (incl 26 isolated colonic)

- - Isolated colonic OR2.63 (1.00-7.11)


Ileocolonic 1.52

(0.82-2.83)

NS increased

Persson93 Case control age and sex

matched

152 - - Isolated colonic RR 3.6 (1.1-12.2)

Small bowel only

0.8 (0.3-2.4)

Ileocolonic 1.7 (0.8-4.0)

NS increased

Katschinski94 Case control pre-

menopausal

90 (incl 30 isolated

colonic)

- - Isolated colonic RR3.2 (1.1-15.3)

Small bowel only RR4.7 (1.6-17.8)

Ileocolonic

RR 3.8 (1.3 -17.0)

NS reduced

Khalili95,96 Cohort – Nurses Health


- - Isolated colonic HR4.13 (1.77-9.68)

Ileal only

HR2.99 (1.06-8.49)

NS increased

Table 3 – Studies of oral contraceptive usage in Crohn’s disease where isolated colonic disease separately identified.

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Author/Ref Year Study design N (isolated colonic

CD)

ASCA IgA

(n/%)

ASCA IgG

(n/%)

ASCA (IgG or IgA) (n/%)

pANCA (n/%)

ompC (n/%)

GP2 UC results in same study

Comments

Duerr115 1991 Prospective 18 - - - 5/18 (28%)

- - pANCA 34/40 (85%) pANCA+ in isolated colonic CD not signif commoner than

diarrhea-predom IBS (4/27 15%)

Cambridge116 1992 Stored sera IBD and healthy controls

18 - - - 1/18 (6%)

- - pANCA 27/50 (54%) pANCA+ in 4/32 CD with small bowel involvt

Joossens117 2002 Prospective follow-up of 97 patients with initial

diag of indeterminat

e colitis

17 NA NA 10/17 (59%)

6/17 (35%)

- - ASCA+ in 3/14 (21%) pANCA+ in 8/14 (57%)

All patients initially indeterminate

Lawrance118 2004 Prospective Caucasian

and Chinese

35 6/35 (18%)

9/35 (26%)

NA NA - - ASCA IgA 6/100 ASCA IgG 11/100

ASCA less likely positive in isolated colonic CD than CD

with ileal involvement

Annese119 2004 Prospective 61 NA NA 25/61 (41%)

- - - ASCA 32/197 (16%) ASCA in CD overall 51%

Ferrante120 2007 Prospective study IBD

plus non-IBD and healthy

controls

70 NA 6% NA 21% 3.5% - ASCA IgG 9.6% pANCA 37%

All antimicrobial abs lower titre in isolated colonic CD than

other CD

Vind121 2008 Prospective cohort

60 NA NA 5/60 (8%) 15/60 (25%)

- - ASCA 14% pANCA 55%

ASCA CD overall 22%

Lakatos122 2009 Cohort 143 NA NA NA NA - - ASCA(either IgA or IgG)+/pANCA-

combination in 9% UC

ASCA(either IgA or IgG)+/pANCA- combination in

52% isolated colonic CD

Bogdanos123 2012 Prospective paediatric

32 NA NA 5/32 (16%) - - 2/32 (6.2%)

GP2 9/102 (8.8%) ASCA 7/102 (7%)

GP2 ab (IgG or IgA) in 49/137 (35.8%) other (nonL2) CD

ASCA 55/137 (40.1%) other (nonL2) CD

Bertin124 2013 Prospective recruited at colonoscopy

67 NA NA 21/67 (31%)

- 15/67 (22%)

- ompC 2/35 (6%) ASCA 5/35 (14%)

Colon mucosal culture supernatant ab measures

discriminated better between L2 CD and UC

Elkadri111 2013 Prospective cohort adults and children

55 NA NA NA but OR 0.25 (0.12-

0.51; P=0.0002) for assocn

with isolated colonic

disease vs other sites

NA but OR 2.27 (1.50 – 4.92;

P<0.03 for

assocn with

isolated colonic disease

42.7% all CD,

isolated CD NA

- ASCA (either IgA or IgG) in 12.1% UC;

62.9% CD; pANCA in 55.6% UC,

14.3% CD; anti-OmpC in 28.0%

UC, 42.7% CD

ASCA positivity less common in isolated colonic CD than other

sites

Table 4. Serological test results in isolated colonic Crohn’s disease and ulcerative colitis.

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*Though the study included patients with isolated colonic CD, results were pooled for patients with colonic involvement #Willing 2010, similar patient cohort to Willing (2009) but sequencing methodology compared to terminal-restriction fragment length polymorphism in Willing (2009). ‡FE index was calculated as [log10 (F/Hc) − log

10 (E/Hc)/log10 (TB/Hc), F being the 16S rRNA gene copies of F. prausnitzii, E the 16S rRNA gene copies of

E. coli, Hc a million of human cells, and TB a million of 16S rRNA gene copies of total bacteria.

Table 5: Studies of mucosal microbiota in Crohn’s disease where isolated colonic disease separately identified

Author/ref Year Specimen type

Number of cases

CD

Ileal CD Ileocolonic CD Isolated colonic CD Ulcerative colitis

Healthy controls

Conclusions

Naftali133 2016 Ileum and colon

31 15 Increased abundance

of Escherichia and reduced

Faecalibacterium; disease activity correlated with abundance of Fusobacterium

8* Similar to colonic CD apart from Faecalibacterium abundance 2.7-fold lower than in isolated colonic CD (not significant)

8* Higher levels of

Faecalibacterium and 2 unidentified

genera of the Clostridiales and

Ruminococceaea; lower levels of

Enterobacteriaceae compared with ileal

NA NA Ileal CD and colonic CD microbiomes

distinct

Haberman13

4 2015 Ileal

biopsy 243

(Paediatric)

180 Persistent reduction in Lachnospiraceae,

Bifidobacteriaceae, Clostridiales, and Erysipelotrichaceae in all forms of CD, with

expansion of Veillonellaceae, Pasteurellaceae, Neisseriaceae,

Gemellaceae, Fusobacteriaceae, and Enterobacteriaceae

63 Persistent reduction in Lachnospiraceae, Bifidobacteriaceae, Clostridiales, and

Erysipelotrichaceae in all forms of CD, with expansion of Veillonellaceae, Pasteurellaceae, Neisseriaceae, Gemellaceae,

Fusobacteriaceae, and

Enterobacteriaceae

73 Increased abundance of Firmicutes phyla

43

No difference between

ileal/ileocolonic CD and colonic CD microbiome

Lopez-Siles132

2014 Ileum and colon

45 19 Reduction in F. prausnitzii, E. coli moderately increased.

13 Reduction in F.

prausnitzii

13 F. prausnitzii

comparable to UC; E. coli commoner

than UC particularly in ulcerated zones

28 F. prausnitzii abundance intermediate between CD

and HC.

28 F. prausnitzii/ E. coli (FE index)‡ allowed differentiation

between ileal CD and other CD

phenotypes. Microbiota changes in colonic CD intermediate

between ileal CD and UC.

Willing#130,13

1 2009,2010

Ileum and colon

14 6 Increased Enterobacteriaceae and Ruminococcus gnavus; decreased Faecalibacteria and Roseburia and compared to healthy controls. Increased E. coli.

8 No reduction in

Faecalibacterium or Roseburia. Some increase in E. coli but less marked than ileo-colonic.

6 Colonic CD microbiome intermediate between ileal CD and healthy controls.

Baumgart129 2007 Ileum 29 13 Increased abundance of Enterobacteriaceae, (E. coli, Shigella) reduction in Lachnospiraceae, (Ruminococci, Roseburia and Coprococci) and Clostridiales ( Faecalibacteria and Subdoligranula)

8 Results not presented separately

8 Enterobacteraciae not increased and Faecalibacteria not

reduced.

NA 7

Ileal CD and colonic CD microbiome were distinct. Colonic CD more closely resembled healthy controls

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Author/Ref N (isolated colonic CD)

5ASA Placebo P value Conclusions

Singleton140 64 CDAI mean change: -77 (+/-27) at 2g/day -81 (+/-31) at 4g/day

CDAI mean change -52 (+/-31)

Overall <0.01 for mesalazine vs

placebo in all CD, P=0.42 for

difference in ileal vs ileocolonic vs

colonic

High placebo response rate in isolated colonic CD so NS if this

group taken alone; better response in ileal only disease

(a) Placebo-controlled trials of oral 5-aminosalicylic acid in isolated colonic Crohn’s disease (i) induction


5ASA relapse rate 12months

Placebo relapse rate 12 months

P value Conclusions

International141 56 32.1% (9/28)

38.9% (11/28)

0.49 5ASA only showed benefit in ileal

disease

Prantera142 18 40% (2/5)

55% (6/?11) extrapolated

from table

NS 5ASA only showed benefit in ileal

disease

Gendre143 48 - - - 5ASA better (P<0.003) than

placebo in all CD patients in remission <3m at onset, no sig difference according to disease location

De Franchis144 36 45% (8/17)(extrapolated

from figure)

45% (9/19)

1.0 5ASA ineffective in ileal, colonic, or

ileocolonic

(a) Placebo-controlled trials of oral 5-aminosalicylic acid in isolated colonic Crohn’s disease (ii) maintenance

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Sulphasalazine remission

Placebo remission

P value Conclusions

Singleton146 20 - - NS Both groups also received tapering

prednisolone. Placebo better

than sulphasalazine in patients with ileal

disease.

Summers147 17 - - 0.006 (comparison of outcome ranks)

Sulphasalazine better than

placebo in colonic CD (also effective in ileocolonic but

not ileal only)

Malchow148 27 31% (4/13)

14% (2/14)

0.4 NS for remission but P<0.01 for

effect when judged by “failure and

relapse”

(b) Placebo-controlled trials of oral sulphasalazine in isolated colonic Crohn’s disease (i) induction


Sulphasalazine relapse rate 12months


P value Conclusions

Singleton146 20 - - NS Sulphasalazine not significantly different from placebo in CD

overall and no relation to disease

location

Summers147 19 - - NS No significant effect (judged by outcome

rank based on CDAI)

(b) Placebo-controlled trials of oral sulphasalazine in isolated colonic Crohn’s disease (ii) maintenance

Author/Ref N (Isolated colonic CD)

Olsalazine relapse /failure rate 12

months

Placebo relapse /failure rate 12

months

P value Comments

Mahmud145 145 65.4% 53.6% 0.035 (Olsalazine worse)

Olsalazine induces diarrhea, no

evidence of efficacy

(c) Placebo-controlled trial of olsalazine in isolated colonic Crohn’s maintenance

Table 6. Trials of 5ASA preparations where data presented separately for isolated colonic Crohn’s disease.

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Comparator Primary end point

Rifaximin remission rate

Placebo remission rate

P value Conclusions

Prantera152 190 active; 76 placebo

(from supplement

table 2)

Placebo Week 12 remission

(CDAI <150)

3 doses: 400mg bd; 800 mg bd; 1200 mg bd; no dose

response overall; pooled doses

remission in 96/190 (51%)

28/76 (37%) 0.04 Rifaximin more effective for colonic than ileal disease

(a) Controlled trial of oral rifaximin

Author/Ref N (isolated colonic

CD)


Metronidazole response rate

Placebo response rate

P value Conclusions

Blichfeldt153 6 Placebo (crossover)

Week 8 response

100% ? NS overall Metronidazole 1g daily

improved symptoms

and lab values in all

six with colonic disease

Sutherland154 12 (4 received 10 mg/kg; 4 received 20mg/kg; placebo)

Placebo Week 16 response

Mean CDAI drop 145, 95% CI 26-

265, n=8

CDAI increased by mean of 61,

n=4

0.05 Metronidazole more effective than placebo in colonic and

ileocolonic disease but not small

bowel disease

(b) Controlled trials of oral metronidazole

Table 7. Trials of antibiotics where data provided separately for patients with isolated colonic Crohn’s disease.

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CD)

Budesonide/ Comparator

Primary end point

Budesonide remission

rate

Comparator remission

rate

P value

Steroid related adverse events

Conclusions

Tromm157 50 (distal colon

excluding rectum) of 307 in

trial

Budesonide 9mg od vs 3mg tds vs

Mesalamine 1.5g tds

Week 8 remission, CDAI≤150

23/30 (76.7%)

10/20 (50%)

0.051 Only 1 budesonide patient with acne, no other steroid-related events

Budesonide borderline signif

better than mesalamine

Bar-Meir158 27 of 201 in trial

Budesonide 9mg od vs Prednisone

40mg od 2wks then

taper


2/10 (20%) 10/17 (58.8%)

0.1 67% Prednisone vs 44% Budesonide

Trend towards better efficacy in colonic disease with Prednisone, similar efficacy if

small bowel involved.

(a) Controlled trials of pH-modified release oral Budesonide


CD)

Prednisone/Comparator Primary end point

Prednis(ol)one remission

rate

Comparator remission rate

P value Conclusions

Summers146 34 of 295 in trial (Pt1)

Prednisone up to 60mg /day (n=8) vs

Azathioprine 2.5 mg/kg (n=9) vs

Sulfasalazine 1g/15kg (n=8) vs

Placebo (n=9)

Week 17 remission

Data presented as rank outcome


0.465 Prednisone not effective

in colon only

disease (but only

n=8 treated)

Malchow147 49 of 215 in trial

(induction data from

table 11)

Sulfasalazine or combination of

sulfasalazine and 6-methyl Prednisolone

Remission by week

18

6/8 (75%) Placebo 2/14 (14%)

Sulphasalazine 4/13 (31%) Combination 13/14 (93%)

<0.01 for Sulfasalazine and

6-methylprednisolone and <0.001 for

combination

All active treatments better than placebo but combination superior to

either agent alone

(b) Controlled trials of oral Prednis(ol)one Table 8. Trials of oral corticosteroids where data provided separately for isolated colonic Crohn’s disease.

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Author Year Type of study

Study agent Total number of patients

Number with

colonic CD

Endpoint Main findings P value (for

colonic vs other sites

unless stated)

Conclusion

Sandborn165 2011 RCT Certolizumab pegol (CZP)

338 120 Week 6 remission (CDAI </=150)

23/63 (36.5%) CZP vs 10/57

(17.5%) placebo

0.052 (colon vs

other locations);

0.034* (active vs placebo)

Probable efficacy in

colonic disease

Arnott166 2003 Cohort Infliximab 74 26 Week 4 response (fall in HBI by >3)

23/26 (88%) response in colonic vs 6/11 (54%) in ileal

0.042 Better efficacy in

colonic than ileal

Laharie167 2005 Cohort Infliximab 44 18 Week 8 response (fall in CDAI by >/= 100)

83.3% colonic CD vs 50% ileal/ileocolonic


colonic than combined

ileal/ileocolonic

Vermeire168 2002 Cohort Infliximab 240 89 Week 4 (luminal) or week 10 (fistulising) response (fall in CDAI by >/=70 or 50% decrease in draining fistulae

81% response colonic CD vs 55% ileal CD vs 74% ileocolonic OR 1.905, 95% CI 1.010 – 3.597



ileal/ileocolonic.

Remission also more likely in isolated colonic

(P=0.019)

Dupont-Lucas169

2016 Cohort

Infliximab 248 (children)

63 Loss of response to maintenance therapy (moderate or severe global assessment requiring cessation of therapy)

Colonic 25/54 (46%) responders or remitters vs ileal/ileocolonic 148/185 (80%). iHR 2.72 (95% CI 1.30-5.71) for loss of response in isolated colonic CD vs other sites

0.008 Isolated colonic disease

more likely to lose

response

Cohen170 2012 Cohort Adalimumab 75 15 Time to dose escalation

13.2 weeks for colonic vs 34.6 weeks for other sites

0.0062 Isolated colonic disease required

earlier dose escalation

Sandborn 171 2013 RCT Vedolizumab 1115 316 (273 active, 43 placebo) Subgroup analysis based on 62 active and 43

placebo.

Remission (CDAI </=150) at week 6 over placebo, Response (CDAI fall >/=100) week 6

Remission difference from placebo: 5.9% for colonic vs 6.7% for ileal vs 8.9% for ileocolonic Response: 10.6% for colonic vs minus 10.4% for ileal vs 7.1% for ileocolonic

0.30 remission

0.23 response

No difference between isolated

colonic and other

Crohn’s for induction

with vedolizumab

Sandborn171 2013 RCT Vedolizumab 461 117 Remission at week 52 over placebo

Remission 8wkly vedo: 18.9% difference from placebo for colonic vs 11.8% for ileal

0.11

0.19


colonic and other

Crohn’s for

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vs 19.9% for ileocolonic Remission 4wkly vedo: 12.7% for colonic vs 25.4% for ileal vs 12% for ileocolonic

maintenancewith

vedolizumab

Table 9: Randomized controlled trials (RCTs) and cohort studies of biological therapy in

Crohn’s disease where data were provided separately for patients with isolated colonic

disease.

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Author/ref Year Nature of

study

Adults/ children

n= Intervention Duration Primary endpoint

Results in patients with ileal

involvement

Results in isolated

colonic CD

P*

Lochs177 1991 RCT Adults 55 (enteral nutrition; 9 colon only);

52 drug treatment

Exclusive Peptisorb

(oligopeptide diet)

4-6 weeks

Remission (CDAI

reduced by 40% or 100

points)

Mean time till

remission 26 days

Mean time till

remission 31 days

NS

Wilschanski178 1996 Retrospective cohort

Children 7-17

65 (5 colon only)

Exclusive Amino-acid or peptide

4weeks or more

Remission PCDAI </=20

Remission 47/60 (78%)

Remission 1/5 (20%)

0.02

Afzal179 2005 Prospective

cohort

Children 8-17

65 (14 colon

only)

Exclusive polymeric

8weeks Remission PCDAI<20



0.01

Buchanan180 2009 Prospective

cohort

Children Median age 12

110 (19 colon only)

Exclusive polymeric (Modulen)

in 105, elemental

in 5

8 weeks Remission (improvt in all domains

of global assesst)

Remission 73/91

(80.2%)

Remission 15/19

(78.9%)

NS

Rubio181 2011 Retrospective cohort

Children Mean age

11

106 (26 colon only)


8 weeks Remission PCDAI<10

Remission 86/106 (81%) overall, colonic data not presented separately but site not correlated with

outcome

NS

De Bie182 2013 Retrospective cohort


76 (18 colon only)

Exclusive polymeric or semi-

polymeric

6 weeks Remission defined as

no diarrhea, pain or wt

loss



NS

Table 10. Results of exclusive enteral nutrition as primary therapy in Crohn’s disease where data provided separately for isolated colonic Crohn’s disease.

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Ileal/Ileocolonic

Crohn’s disease

Isolated colonic

Crohn’s disease

Ulcerative colitis

Sex Slightly commoner in females (c55%)

Commoner in females (c65%)

Equal or slight male predominance

Genetics Crohn’s-associated genotype including

NOD2/CARD15

Genotype midway between Crohn’s and

UC Associated with HLA-DRB1*01:03 but not

NOD2/CARD15

UC-associated genotype including HLA-DRB1*01:03

Smoking Marked association Worsens prognosis

Weak association Possibly worsens

prognosis

Marked negative association

Oral contraception Positively associated Positively associated Positively associated (mainly in smokers)

Serology ASCA commonly positive

pANCA usually negative

ASCA less commonly positive than

ileal/ileolonic CD pANCA positive in

minority

ASCA usually negative pANCA commonly

positive

Mucosa-associated Microbiota

Marked changes commonly including

increased Proteobacteria (eg E.

coli) and Fusobacteria, reduced Firmicutes (eg

F. prausnitzii

Intermediate changes similar to ileal/ileo-colonic CD but less

consistent

Modest changes, including slight

increase in E. coli but no reduction in F.

prausnitzii

Response to mesalazine

No efficacy No efficacy Good efficacy

Response to anti-TNF Good efficacy Good efficacy – probably better than for ileal/ileocolonic

Good efficacy

Response to excusive enteral nutrition

Good efficacy Probably good efficacy but mixed reports

No efficacy

Surgery rate and type

Required in majority Required in minority Segmental colectomy

effective High failure for pouch-

anal reconstruction

Required in minority Segmental colectomy

not effective Low failure for pouch-

anal reconstruction

Table 11. A summary of the distinguishing features of the three inflammatory bowel diseases: ileal/ileocolonic Crohn’s disease, isolated colonic Crohn’s disease, ulcerative colitis.

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Comparison between Crohn’s disease genetic risk score and ulcerative colitis genetic risk score for different locations of Crohn’s disease, ulcerative colitis and IBD unclassified (from Cleynen et al,17 with permission. This shows that isolated colonic Crohn’s lies approximately equidistant genetically between ileal Crohn’s

disease and ulcerative colitis. Crohn’s disease similarly ov 238x131mm (300 x 300 DPI)

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Isolated colonic Crohn’s as percentage of all Crohn’s disease by year in studies reporting sequential data from the same centres or geographical areas.

total Crohn’s from 1970 to 1

212x148mm (300 x 300 DPI)

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Isolated colonic Crohn’s disease as percentage of all Crohn’s disease by year in all studies. (p=0.02 by polynomial regressi 238x192mm (300 x 300 DPI)

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168x148mm (300 x 300 DPI)

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Recent advances in clinical practice: a systematic review of isolated colonic Crohn’s

disease – the third inflammatory bowel disease?

5355 words

Sreedhar Subramanian (1), Anders Ekbom (2), Jonathan M Rhodes (1).

1. Institute of Translational Medicine, University of Liverpool,The Henry Wellcome Laboratory,Nuffield Building,Crown St.,LiverpoolL69 3GE, UK 2. Department of Medicine, Karolinska Institute, Solna 171 76, Stockholm, Sweden

Corresponding author: Jonathan M Rhodes [email protected]

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ABSTRACT

The genetics of isolated colonic Crohn’s disease place it approximately midway between Crohn’s disease with small intestinal involvement and ulcerative colitis, making a case for considering it as a separate condition. We have therefore systematically reviewed its epidemiology, pathophysiology, and treatment. Key findings include a higher incidence in females (65%) and older average age at presentation than Crohn’s disease at other sites, a mucosa-associated microbiota between that found in ileal Crohn’s disease and ulcerative colitis, no response to mesalazine, but possibly better response to anti-TNF than Crohn’s disease at other sites. Diagnostic distinction from ulcerative colitis is often difficult and also needs to exclude other conditions including ischaemic colitis, segmental colitis associated with diverticular disease and tuberculosis. Future studies, particularly clinical trials, but also historical cohorts, should assess isolated colonic Crohn’s disease separately. INTRODUCTION

Diagnosis of Crohn’s disease is often contentious when ileal involvement is lacking. This has a long history. Colitis with skip lesions and rectal sparing was considered in 19301 as “regional migratory ulcerative colitis”. Crohn’s classic 1932 paper did not include cases with colonic involvement2 although non-tuberculous granulomatous involvement of ileum and colon had been reported in 19233 and later by others.4, 5 From the 1930’s to the 1950’s, colitis without rectal or terminal ileal involvement was usually designated “regional” or “segmental” colitis.6 The British surgeon Wells first used “Crohn’s disease of the colon” when describing cases of granulomatous regional colitis in 1952.7 Initially this was not widely accepted and Kirsner (1960) continued to refer to cases with submucosal granulomata and skip lesions as ulcerative colitis.8 Identification of Crohn’s disease of the colon separately from ulcerative colitis was strongly reinforced by Lockhart-Mummery and Morson, (1960) who described 25 cases with features including non-bloody diarrhoea, anal fistulae, rectal sparing, skip lesions and strictures.9 Histopathology showed submucosal giant cell granulomata, fibrous thickening, and regional lymph node enlargement. This paper caused a “paradigm shift” that has led practice since. It was reinforced the following year when Cornes and Stecher reported 45 patients with isolated colonic Crohn’s disease, with fistulation in nearly two thirds, and skip lesions in 20% .10 Later evidence that colonic Crohn’s disease, unlike ulcerative colitis, might be improved by faecal diversion,11, 12 treatable by segmental resection13, and associated with poor outcomes after ileal pouch-anal anastomosis,14 seemed to confirm even more securely its position as a form of Crohn’s disease and distinct from ulcerative colitis. Distinction of colonic Crohn’s disease from ulcerative colitis may be difficult though. The term “indeterminate colitis” was introduced to describe cases, “10-20%”, where, after colectomy and examination of the resected colon, a clear diagnosis is not possible.15 The term was often incorrectly applied to patients without colectomy until “inflammatory bowel disease unclassified” (IBD-U) was recommended for such cases.16

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The scene is now changing again – extensive data show that isolated colonic Crohn’s disease is genetically separable from Crohn’s disease involving the small intestine.17 When the ratio of Crohn’s-associated genes to ulcerative colitis-associated is compared with disease phenotype isolated colonic Crohn’s disease lies approximately midway between ileal Crohn’s and ulcerative colitis. IBD-U, although statistically separable from ulcerative colitis overlaps it considerably and ileo-colonic Crohn’s disease similarly overlaps ileal Crohn’s disease (Figure 1). This finding led to recommendation that Crohn’s disease with ileal involvement (ileal and ileocolonic), isolated colonic Crohn’s disease and ulcerative colitis should be considered as three separate conditions. It is therefore timely to review the epidemiology, genetics, serology, microbiology, and response to treatment of isolated colonic Crohn’s disease and to reconsider whether this “evidence” favours isolated colonic Crohn’s disease as a variant of Crohn’s disease, as a variant of ulcerative colitis, or as a separate condition. METHODS

The medical literature was searched using National Library of Medicine/Pubmed to 1st December 2015 using the terms “colonic and Crohn’s” “Crohn’s and colitis” “epidemiology and Crohn’s”. We conducted additional searches for “smoking and Crohn’s disease” and “oral contraception and Crohn’s”. Later (to 1st June 2016) additional searches for “Crohn’s” and each of the therapies covered were performed. After removal of duplicates and screening of abstracts for relevance, 840 were selected for further review (Supplementary Figures 1 &2). Whilst the literature search was fully systematic, the subject of this review is necessarily much broader than that of a conventional systematic review. We have only included full publications in english language and have not attempted to judge quality of the data. For epidemiological studies we included all reports that (a) contained data on at least 100 patients with Crohn’s disease and (b) included separate data for isolated colonic Crohn’s disease (Montreal classification L2). Where published studies had overlapping patient base and time period we used only the more completely described data set to avoid duplication. For other aspects of the review (genetics, serological testing, response to therapies and association with environmental factors) we included all studies that identified isolated colonic Crohn’s disease separately. For therapeutic studies we have separately identified data that have been obtained from randomized clinical trials and those that have been obtained from cohort studies. It should be noted that, whereas pure ileal Crohn’s and pure colonic Crohn’s should be readily distinguished by a comprehensive diagnostic assessment including ileal intubation, incomplete assessment could mislabel ileocolonic as colonic. This should be taken into account particularly in respect of older studies but we have taken care to ensure that all data included here regarding isolated colonic disease relate to patients thought at the time of publication not to have ileal disease. Statistical analysis was performed using StatsDirect3 v 3.0.171 StatsDirect Ltd, UK. PATHOLOGY, DIFFERENTIAL DIAGNOSIS, AND DISEASE COURSE – DEFINING THE

CONDITION

The histological features of isolated colonic Crohn’s disease were first defined by Lockhart-Mummery and Morson.9 They labeled patients with this diagnosis because “they had the same characteristic pathology in the large intestinal lesions as that described by Hadfield18 for the disease as it affects the small intestine”. Gross appearances of the colon following

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colectomy include less sharp demarcation of ulceration than typically seen in ulcerative colitis and with areas of intact intervening mucosa. In some cases, very marked fibrous thickening with associated stricturing was present. Fibrosis and oedema sometimes extended into the pericolic fat and enlargement of regional lymph nodes was marked. Warren later split the macroscopic features into three patterns: isolated rectal disease; stricturing colonic disease; diffuse colitis – usually with rectal sparing, and noted that approximately 75% develop perianal pathology during their disease course.19 Microscopic features described by Morson included discontinuous inflammation and ulceration which could extend into the submucosa or deeper into the wall as the basis of fistula formation, plus focal crypt irregularity. Non-caseating epithelioid granulomas were present in the majority, distributed through all layers of the bowel wall as well as regional lymph nodes. Other features included submucosal lymphangiectasia and neuromatous hyperplasia.20 It has subsequently been noted that the earliest lesions – aphthous ulcers – which usually overlie lymphoid follicles, are preceded by a “red ring” sign on colonoscopy, biopsy of which reveals a lymphoid follicle surrounded by reactive hypervascularisation.21 Histopathology alone is diagnostic only in the minority – in a series of 103 cases of Crohn’s colitis, diagnosis was determined by microscopy alone in 28%, by distribution (rectal sparing and/or discontinuity) alone in 22% and by combination of the two in 50%.22 Particularly discriminatory features suggesting Crohn’s colitis rather than ulcerative colitis include granulomata, submucosal inflammation, and relative preservation of goblet cells.23,24 At an international workshop expert pathologists “correctly” identified only 64% of cases with Crohn’s colitis and 74% with ulcerative colitis25 leading the European consensus on histopathology of inflammatory bowel disease (2013) to note that “accurate discrimination between the two diseases (Crohn’s colitis and ulcerative colitis) is not yet optimal amongst expert gastrointestinal pathologists”. Given that inflammatory disease pathogenesis is multifactorial an alternative interpretation would be that there is a continuous phenotypic spectrum that runs through from “typical” ulcerative colitis, through IBD-unclassified to “typical” Crohn’s colitis. Early studies reported an additional incidence peak of Crohn’s disease in the elderly resulting from cases particularly affecting the sigmoid colon.26 Following the later clarification of segmental colitis associated with diverticular disease (SCAD) this seems probably attributable to SCAD. SCAD can be indistinguishable histologically from inflammatory bowel disease and includes a “Crohn’s-like” variant with granulomata.27 This reflects emphasis often placed on the diagnostic specificity of the granuloma. However, granulomas are only found in colonoscopic biopsies at diagnosis in about 66% of adults with colonic Crohn’s disease, falling to 18% at follow-up.28 Moreover granulomas, particularly in association with crypts, can be found in ulcerative colitis.29 Other forms of colitis that may need to be considered in the differential include ischemic colitis (see earlier) and infections including amoebiasis and tuberculosis but it is beyond the scope of this review to consider these further. Localisation of disease to the colon remains fairly constant over time. The largest published data set by far is the 16,902 Crohn’s disease cohort, including 2,933 with isolated colonic disease, in the recent genotype/phenotype association study.17 This confirmed previous

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reports of low rates of progression to ileo-colonic disease (5-14% over 7-10 years). 30-32 Although luminal narrowing is common, stricturing (B2 disease) as defined in the Vienna/Montreal classifications requires the presence of prestenotic dilatation or obstructive signs or symptoms and this very rarely occurs, eg 0/45 cases in a Belgian series 33 whereas penetrating disease (B3) as defined by the Vienna classification (ie including peri-anal fistulae) occurred in 23% in the same series, less frequently than in patients with ileal disease (46%; P=0.0003) or ileocolonic (28.6%; NS). The much larger genotype/phenotype association study confirmed that cumulative probability of progression to B2 and B3 combined over ten years was substantially lower in colonic disease – 23%, than in ileocolonic disease - 62%, or ileal disease - 68%.17 The risk of surgery (discussed later) was also much lower at ten years (22%) than for ileo-colonic (42%) or ileal disease (62%). A recent meta-analysis showed that colon cancer risk in isolated colonic Crohn’s disease is similar to ulcerative colitis of equivalent extent with a pooled standardized incidence ratio (SIR) of 1.7; 0.9-2.6 95%CI (population based data) compared with SIR 1.8; 1.2-2.4 for ulcerative colitis but rising to SIR 18.2; 7.8-35.8 for extensive colonic Crohn’s disease in a referral centre population compared with SIR 21.6; 15.0-31.0 for extensive ulcerative colitis.34

EPIDEMIOLOGY

Changes over time

Studies reporting sequential data from a single centre or region show interesting time trends. Studies from UK35,36 and Sweden37 reported a marked increase in isolated colonic Crohn’s as a proportion of total Crohn’s from 1970 to 1990 (Figure 2A) whereas later studies, particularly from France38 have shown a downward trend since 1990. When looked at across all geographical areas, (Table 1), although there is no obvious difference in proportion of isolated colonic disease between countries or regions, there is a similar time trend with increase in isolated colonic disease between 1960 and 1990, peaking at an average of about one third of all Crohn’s disease cases, and decreasing since (p=0.02 by polynomial regression, Figure 2B).

Sex variation

We found eight studies which stated the sex distribution of patients with isolated colonic Crohn’s disease. In all but one the female preponderance was equal or greater to that reported from the same study for total Crohn’s disease (Table 1) – isolated colonic Crohn’s disease averaging 65.1% female, compared with Crohn’s disease excluding isolated colonic 55.3% female (P=0.027 by paired t test). Age at diagnosis

Age at diagnosis of isolated colonic Crohn’s disease (in seven studies; Table 1), has a median between 28 and 45, around 10 years older than generally reported for all Crohn’s – eg median 25 years in the 16,902 patients studied by Cleynen et al17. Older age of isolated colonic versus other sites of Crohn’s disease was also confirmed by the IBDchip European Project.85 The preponderance of isolated colonic disease amongst children with very early onset Crohn’s disease is discussed later. Smoking

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Cigarette smoking is associated with increased risk for development and progression of Crohn’s disease but reduced risk for ulcerative colitis. Smoking is more strongly associated with risk for ileal and ileo-colonic Crohn’s disease than for isolated colonic disease (Table 2). Only one study (of nine)79 reported a higher rate of smoking amongst patients with isolated colonic Crohn’s disease. If the South African data84 which reported exceptionally high rates (73%) across all groups are excluded, the other studies report rates for smoking amongst patients with isolated colonic disease that averaged 37.8% compared with 49.8% (P=0.008 by paired t test) for other Crohn’s disease sites. This smoking rate is probably slightly higher than for the general population – approximately 30% European adults were smokers in 2008 (WHO).86 Smoking worsens prognosis of Crohn’s disease overall and cessation of smoking improves it.87,88 This has been studied less in isolated colonic disease but the conclusion is similar. The largest study80 included 688 patients with Crohn’s colitis, 978 with ulcerative colitis and 118 with “indeterminate” colitis. Sixty-one per cent of patients with ulcerative colitis or indeterminate colitis had stopped smoking before disease onset compared with only 12% in isolated colonic Crohn’s disease. In women but not men with isolated colonic disease the risk of needing immunosuppression was increased amongst smokers (10-yr cumulative risk 48% in non-smokers vs 58% in smokers, P<0.01). An earlier study74 showed that smokers with Crohn’s colitis relapsed approximately 50% more often (P=0.028) and with more pain (P<0.007) than non-smokers. Thus smoking at best has a neutral effect on isolated colonic Crohn’s disease but more likely is harmful. Oral contraception

Meta-analysis of 14 studies, with adjustment for smoking, showed a relative risk of 1.51 (95%CI 1.17-1.96, P=0.002) for Crohn’s disease amongst women currently taking oral contraception89. The relative risk for ulcerative colitis was also increased at 1.53 (1.21-1.94, P=0.001). Six of the seven studies that reported risk associated with oral contraception separately for isolated colonic disease found a significant association (Table 3) with relatively high odds ratio (2.63), risk ratios (3.6 and 3.23) or hazard ratio (4.13). The sole exception91 only included 8 cases with isolated colonic Crohn’s disease and showed no overall association between oral contraception and risk for Crohn’s disease. Excluding the latter study91, five of the other six show higher risks amongst oral contraceptive users for isolated colonic Crohn’s than for other sites.

Oestrogen-associated ischaemic colitis as a confounder

An early study from Birmingham50 reported patients with apparent oral contraceptive-associated colonic Crohn’s disease who had non-granulomatous colitis with rectal sparing. Ischaemic colitis is a rare but recognized complication of oral contraception that might cause diagnostic confusion. 97,98,99 Most cases have a short duration with typical features of ischaemic colitis including abdominal pain, and rectal bleeding. Colonoscopy shows mucosal friability but no linear ulceration and the proximal colon and rectum are typically normal. Such cases should be readily distinguishable from colonic Crohn’s disease but Tedesco100

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reported five cases of oral contraceptive-associated colitis with features that overlapped more with colonic Crohn’s disease than ischaemic colitis. Moreover, colonic “thumbprinting”, a characteristic feature of ischaemic colitis, has been reported in Crohn’s disease.101 It is unclear whether diagnostic overlap with milder cases of oral contraceptive-associated ischaemic colitis contributes to the female preponderance of isolated colonic Crohn’s disease. If it does then the change to lower oestrogen dosing in later versions of the contraceptive pill might be a plausible explanation for the apparent fall off in cases in recent decades.102 Clinicians should be aware of the possible associations between oral contraception and inflammatory bowel disease or ischaemic colitis and advise patients accordingly – such advice should usually include at least a temporary cessation of oral contraception to assess impact on the colitis.

GENETICS

The strongest genetic association with IBD is the link between NOD2/CARD15 and Crohn’s disease. Meta-analysis of 42 studies showed that this association was stronger for Crohn’s disease with small bowel involvement than for those without (OR 2.53; 95%CI 2.01-3.16).103

Subsequent study of 1528 patients with Crohn’s disease from 8 centres (in 7 European countries) (IBDchip) confirmed the association of NOD2/CARD15 with ileal involvement and also showed that Interleukin23 receptor polymorphisms were more strongly associated with isolated colonic Crohn’s (OR 2.20; 95%CI 1.17-4.57).85 The most consistent genetic link with ulcerative colitis is with the rare Major histocompatibility Complex (MHC) / Human Leucocyte Antigen (HLA) Class II allele HLA-DRB*0103. This occurs in less than 2% in European and white North American populations and is absent in the Japanese. It is strongly associated with colonic Crohn’s disease where it is present at up to 32% frequency with Odds Ratios for isolated colonic disease of 5.1-18.5 compared with Crohn’s disease at other sites.104 The largest study to compare genetic associations with Crohn’s disease phenotype included 19713 patients from 49 centres across 16 countries in Europe, North American and Australasia.17 This confirmed that the strongest association with isolated colonic Crohn’s disease was HLA-DRB1*01:03 (p=1.47 x 10-23, ileal vs colonic OR 0.32, 95%CI 0.29-0.41; ileocolonic vs colonic OR 0.47, 95%CI 0.39-0.57). The only other loci that were significant across all analyses in this study were NOD2 (16q12), again associated with increased risk for ileal involvement (OR ileocolonic vs colonic 1.61,1.59, and 1.89 for the three NOD2 polymorphisms tested) and also MST1 (macrophage stimulating -1 that encodes a protein which induces macrophage phagocytosis) polymorphisms which were more weakly associated with ileal involvement (OR 1.07 -1.10 according to polymorphism and whether comparing ileal or ileocolonic with colonic disease). When overall genetic risk scores for Crohn’s disease and ulcerative colitis were computed as a ratio and compared with phenotype, isolated colonic Crohn’s disease was found to be approximately “balanced” in respect of Crohn’s disease versus ulcerative colitis genetic risk factors (Figure 1). It was found though that even the combination of smoking status with the strongest genetic predictors could only explain 6.8% of the variance for disease location. ISOLATED COLONIC CROHN’S DISEASE IN CHILDHOOD AND SINGLE GENE DISORDERS

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Amongst children with very early onset Crohn’s disease there is a marked preponderance of cases with isolated colonic disease eg 76.5% before age 5105 and 42% before age 8.106 Amongst younger cases there is a strong male preponderance – eg 1.6:1 across all Crohn’s disease presenting <5105 and some of this is accounted for by X-linked single gene disorders. The first such condition to be identified was X-linked Chronic Granulomatous Disease. Chronic Granulomatous Disease is associated with defects in neutrophil function leading to skin lesions and in around 40% with a form of inflammatory bowel disease that is indistinguishable from Crohn’s disease, typically with predominant colorectal and perianal involvement .107 It is due to mutations in one of four NADPH oxidase complex component genes of which the commonest (CYBB) located on the X chromosome accounts for about 65% cases. Rapid developments in DNA sequencing have allowed identification of over 50 further single gene disorders that present as inflammatory bowel disease, typically as colonic disease and with presentation before age 6, defined as Very Early Onset IBD or VEO-IBD.108 VEO-IBD cases account for 4-10% of paediatric inflammatory bowel disease.109 One of the commoner single gene variants is in the coding region of X-linked inhibitor of apoptosis protein (XIAP) that accounts for about 4% of male patients with paediatric onset Crohn’s disease.110

SEROLOGY INCLUDING ANTI-MICROBIAL AND ANTI-NEUTROPHIL ANTIBODIES

Anti-microbial antibodies such as Anti-Saccharomyces cerevesiae (ASCA) and antibodies to outer membrane protein (ompC) are found less often and/or at lower titre in isolated colonic Crohn’s than in other Crohn’s phenotypes.111 Meta-analyses confirm this particularly for ASCA.112-114 Average sensitivity of ASCA for isolated colonic Crohn’s disease diagnosis is 31% but with a wide range (8-59%) and an average 14% positivity rate in ulcerative colitis (Table 4). The clinical utility of ompC antibodies has been less studied but reported positivity/sensitivity in isolated colonic Crohn’s disease is substantially lower than that for ASCA. Anti-neutrophil antibodies, particularly an atypical peri-nuclear antibody (pANCA), are present in around 55% of patients with ulcerative colitis114 and 23% of patients with isolated colonic Crohn’s disease (Table 4). This compares with pANCA positivity of around 11% in Crohn’s disease overall and 3% in non-IBD controls.114 A combination of positive ASCA and negative pANCA is more discriminatory eg positivity rate in isolated colonic Crohn’s disease of 52% compared with 9% in ulcerative colitis122 but is still insufficiently predictive for routine clinical use.125 Thus the frequency in isolated colonic Crohn’s disease of both ASCA and pANCA antibodies lies somewhere in between that found in Crohn’s disease with ileal involvement (more likely ASCA+, and pANCA-) and that found in ulcerative colitis (more likely ASCA- and pANCA+).

MICROBIOTA

The faecal microbiota in active inflammatory bowel disease is commonly dysbiotic with reduced bacterial diversity.126,127 This could be secondary to inflammation yet still significant

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in maintaining chronicity. The large study of pre-treatment Crohn’s disease by Gevers showed only a mild dysbiosis in the faecal microbiota and much greater separation of Crohn’s disease from healthy controls when the mucosa-associated microbiota was studied.128 Ileal and rectal mucosal samples typically showed a reduction in Firmicutes such as Faecalibacterium prausnitzii and an increase in Proteobacteria such as Escherichia coli as well as in Veillonella, Haemophilus and Fusibacteria. This confirmed many previous studies showing an increase in mucosa-associated E. coli in Crohn’s disease as well as several showing a reduction in F. prausnitzii

129-132. The faecal and mucosa-associated microbiota in isolated colonic Crohn’s disease are generally closer to that of healthy controls than is found in patients with ileal or ileocolonic Crohn’s disease (Table 5). Thus Baumgart et al

129 found that an increase in ileal mucosa-associated E. coli and reduction in ileal F. prausnitzii was only present in patients with Crohn’s disease who had ileal involvement and not in those with isolated colonic disease. Similarly, a study of twins with/without Crohn’s disease showed that faecal microbial diversity was only reduced and Proteobacteria increased in patients with ileal involvement and not in patients with isolated colonic disease.130 A previous report by the same group also showed a reduction in F. prausnitzii in Crohn’s patients with ileal involvement but not in isolated colonic disease.131 Both the twin study by Willing131 and the large study in children128 and adolescents134 did however show differences between the mucosa-associated microbiota in isolated colonic Crohn’s disease and ulcerative colitis. 16sRNA pyrosequencing of mucosal samples133 confirms the increase in E. coli and reduced F.

prausnitzii in Crohn’s disease with ileal involvement with milder changes in isolated colonic disease, although the latter did show some reduction in F. prausnitzii compared with healthy controls. This study also confirmed that the mucosa-associated microbiota are consistent at different sites from ileum to rectum in the same individual. In conclusion, mucosa–associated microbiota changes in Crohn’s disease are more marked than faecal changes. The microbiota in isolated colonic Crohn’s disease, show changes that tend to be less marked and less consistent than those found in Crohn’s disease with ileal involvement.

RESPONSE TO TREATMENT

Mesalazine

Systematic reviews show no convincing benefit of oral mesalazine (5-aminosalicyclic acid) over placebo either in induction of remission or in maintenance of medically induced remission in Crohn’s disease as a whole1345138 although they may have a modest benefit in maintaining surgically-induced remission.139 Sulphasalazine (sulphapyridine linked via azo bond to 5-aminosalicylate) has possible modest efficacy in induction of remission.134, 136 Amongst trials that have reported data separately for isolated colonic Crohn’s disease, only one trial studied the effect of oral mesalazine in remission induction140 and four studied its effect in maintenance of medically-induced remission141-144 (Table 6). In none of these was

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mesalazine significantly more effective than placebo but in two studies141,142 there was a weak signal suggesting a better response in ileal disease. A single trial of olsalazine showed worse results than for placebo, probably because of drug-related diarrhea.145 Sulphasalazine was no better than placebo in two trials of maintenance146,147 but there was a weak signal of efficacy in remission induction in two trials147,148 but these only studied 17 and 27 patients with isolated colonic disease respectively (including placebo). Apart from case reports there have been no published studies of rectal mesalazine in isolated colonic Crohn’s disease. It can be reasonably concluded that mesalazine and olsalazine do not have efficacy in isolated colonic Crohn’s disease. Sulphasalazine possibly has some efficacy in remission induction. Antibiotics

Systematic reviews suggest a beneficial effect for antibiotics in the induction of remission for Crohn’s disease though these have included diverse antibiotics and small trials.149-151 The largest study to date is for rifaximin.152 Three doses were tested: 400, 800, 1200mg or placebo twice daily for 12 weeks with good efficacy overall but no dose response. Amongst patients with isolated colonic disease higher remission rates (51%) were found for rifaximin (pooled doses) than for placebo (37%) and efficacy was better in this group than for other disease sites (Table 7). Metronidazole has also shown better efficacy in isolated colonic Crohn’s disease but based on very small numbers (Blichfeldt153: n=6 crossover; Sutherland154: 8 active and 4 placebo). In a study of 134 patients randomly assigned to ciprofloxacin and metronidazole, both 500mg twice daily, or placebo in combination with budesonide 9mg daily155 a trend was seen towards benefit in patients with colonic involvement compared with those without but separate data were not reported for patients with isolated colonic disease. A large randomized trial of long duration (up to 2 years) antibiotic therapy (clarithromycin, rifabutin and clofazimine) targeted against Mycobacterium avium paratuberculosis in patients also receiving tapered prednisolone showed short term efficacy with 66% active in remission at 16 weeks compared with 50% placebo (P=0.02) and 39% relapsed by 12 months compared with 56% placebo (P=0.054).156 No differential response was seen according to disease location but data were not presented separately for patients with isolated colonic disease.

Rifaximin and metronidazole thus show some evidence of efficacy in patient with isolated colonic Crohn’s disease and antibiotics tend to perform better in this group of patients than in Crohn’s disease at other sites but based on very small data sets. Further trials are clearly needed.

Corticosteroids

Given the widespread use of corticosteroids in Crohn’s disease the quality of evidence for their efficacy is surprisingly poor. There have only been two placebo-controlled trials of standard glucocorticosteroids.147,148 Each of these included only 8 steroid-treated patients with isolated colonic disease (Table 8) with one trial147showing no benefit and the other148showing efficacy. There has never been a trial to assess dose-responsiveness to

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conventional corticosteroids in Crohn’s disease so optimal dosage is unknown. More data are available for budesonide but trials have focused predominantly on patients with ileal or ileo-colonic disease so data in isolated colonic disease are again very sparse. The data from one comparison with mesalazine157, support efficacy in isolated colonic Crohn’s disease, possibly with a weaker effect than conventional corticosteroids158, but reduced corticosteroid side-effects.

Anti-TNF

None of the randomised trials of infliximab159,160 or adalimumab161-164 reported subgroup analyses of outcomes based on disease location. In a randomised, placebo controlled trial of certolizumab pegol, patients with colonic (OR 2.39, 95% CI 0.99-5.75, P=0.052) and ileocolonic disease (OR 2.07, 95% CI 1.01-4.28, P=0.048) were more likely to achieve remission at week 6 compared to ileal disease (OR 0.42, 95% CI=0.18-0.99, P=0.048)165(Table 9) Several cohort studies have assessed colonic disease location as a predictor of response to anti-TNF agents, four with infliximab and one with adalimumab. Three cohort studies assessing induction therapy with infliximab166-168 all showed better response rates in isolated colonic disease than for disease at other sites. Paradoxically, cohort studies of infliximab maintenance in children169 and of adalimumab maintenance in adults170 both showed higher risk of lost response or dose escalation in isolated colonic disease. Overall, the evidence supports good efficacy for anti-TNF therapy in induction of remission in isolated colonic Crohn’s disease but possibly with a higher subsequent rate of loss of response.

Vedolizumab

In the combined induction and maintenance study of vedolizumab there was no significant difference in efficacy in isolated colonic disease compared with other locations.171 (Table 9)

Enteral nutrition

Exclusive enteral nutrition is effective as primary therapy in patients with active Crohn’s disease172,173 and partial enteral nutrition has shown efficacy in maintenance of remission.174 In ulcerative colitis total parenteral nutrition and bowel rest are ineffective175 and comparison of enteral with parenteral nutrition showed no difference in efficacy176 implying no efficacy for enteral nutrition either. Whether enteral nutrition is effective as primary therapy in isolated colonic Crohn’s disease is controversial. Relatively few studies provide separate data on patients with isolated colonic Crohn’s disease (Table 10). Five of the six studies are in children. Two studies178,179 report poorer results in children with isolated colonic disease compared with those with small intestinal involvement. Numbers are small though (19 cases of isolated colonic disease across the two trials) and the other studies (including 72 cases of isolated colonic disease across four trials) found no significant difference in remission rates for those with isolated colonic disease compared with other

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sites. Further trials of exclusive enteral nutrition are needed in patients with isolated colonic disease.

Surgery

Faecal diversion

Colonic Crohn’s disease commonly responds to “bowel rest” induced by a defunctioning ileostomy whereas ulcerative colitis does not.11, 12 Instillation of unfiltered ileostomy contents into the defunctioned colon induced relapse whereas instillation of content that had passed through a 0.22micron pore diameter filter did not, implying a role for bacteria in pathogenesis.183 Defunctioning ileostomy has become less commonly performed for the treatment of uncomplicated colonic Crohn’s disease since it was shown that at least 50% relapsed after continuity was restored.184

Resection

The cumulative risk of surgery for isolated colonic Crohn’s disease is reported as 22-33% by 10 years after diagnosis compared with around 75-90% for ileal disease.17,67 Partial resection, either right hemicolectomy for proximal disease or a segmental resection for more distal disease has been shown to be successful therapy for colonic Crohn’s disease185,

186 as is colectomy with ileo-rectal anastomosis for more extensive disease if the rectum is uninvolved187,188. Approximately 75% of patients with ileo-rectal anastomosis will still have a functioning anastomosis after 10 years and about two thirds of those treated by segmental resection will not have required a further resection.188 Recurrence rates are similar after either procedure.189 This contrasts with left-sided ulcerative colitis, where the tempting option of left hemicolectomy with right-sided colo-anal anastomosis consistently fails, usually with rapid recurrence of colitis in the retained colon.190 It should be noted though that segmental resection for colon cancer complicating colonic Crohn’s disease has been associated with high (39%) risk for metachronous colon cancer191 suggesting that panproctocolectomy might be a safer option for such patients.

Ileo-anal pouch reconstruction

Crohn’s disease has generally been considered a contra-indication for restorative ileo-anal pouch surgery and even in selected patients pouch failure of 57% has been reported from the UK.192 Others have suggested that it may be successful in very carefully selected patients. Thus, a series of 3,707 patients with ileal-pouch anal anastomosis from the Cleveland Clinic included 150 with Crohn’s disease, of whom 32 had a pre-operative diagnosis, the remainder diagnosed by post-operative histopathology or on follow-up. Amongst 59 patients with Crohn’s disease reaching 10 year follow-up, pouch survival was 80%.193 Forty nine of 132 patients (37%) needing pouch excision had a histological diagnosis of Crohn’s disease. Considering that a pre-operative diagnosis of Crohn’s disease was only present in less than 1% of patients receiving pouch-anal anastomosis these data do not make a strong case for this procedure in patients with a definite diagnosis of colonic Crohn’s disease.

CONCLUSION

Current data suggest that the genetics, microbiota, serology and smoking association of isolated colonic Crohn’s disease lie between those of ileo/ileocolonic Crohn’s disease and

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ulcerative colitis and make a strong case for this phenotype being considered separately (Table 11). Genetic data in particular show good separation from ileal/ileocolonic Crohn’s disease and the low rate of progression from isolated colonic to ileo-colonic disease help to justify this distinction. There is a disappointing paucity of good quality therapeutic data but the lack of response to mesalazine, whose target cell is the surface epithelium, suggests a different pathophysiology to ulcerative colitis and there are important differences from ulcerative colitis in surgical outcomes, including a good response to segmental resection in selected cases and a generally poor response to pouch reconstruction. Taken together this implies a compelling need for isolated colonic Crohn’s disease to be identified separately from ileal/ileocolonic disease and from ulcerative colitis. This is particularly important when future therapeutic trials are designed and when cohort studies are reported. Acknowledgements: Funding: None Conflicts of interest: SS has received speaker fee from MSD, Actavis, Abbvie, Dr Falk pharmaceuticals, Shire and received educational grant from MSD, Abbvie, Actavis and is an advisory board member for Abbvie, Dr Falk pharmaceutics, Janssen and Vifor pharmaceuticals. JMR is or has been a member of advisory boards for Atlantic, Pharmacosmos, Procter and Gamble, Vifor and Falk, has received speaking honoraria from Abbott, Falk, Ferring, Glaxo Smith Kline, Merck, Procter and Gamble, Schering Plough, Shire, and Wyeth, and with the University of Liverpool and Provexis UK, holds a patent for use of a soluble fibre preparation as maintenance therapy for Crohn’s disease plus a patent pending for its use in antibiotic-associated diarrhoea. Provenance and peer review: Commissioned; externally peer reviewed.

LEGENDS TO FIGURES:

1. Comparison between Crohn’s disease genetic risk score and ulcerative colitis genetic risk score for different locations of Crohn’s disease, ulcerative colitis and IBD unclassified (from Cleynen et al,17 with permission. This shows that isolated colonic Crohn’s lies approximately equidistant genetically between ileal Crohn’s disease and ulcerative colitis.

2A. Isolated colonic Crohn’s as percentage of all Crohn’s disease by year in studies reporting sequential data from the same centres or geographical areas. 2B. Isolated colonic Crohn’s disease as percentage of all Crohn’s disease by year in all studies. Supplementary Files 1. PRISMA flow diagram. 2. PRISMA checklist.

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Colitis 2016;10:795-804. 170. Cohen RD, Lewis JR, Turner H et al. Predictors of adalimumab dose escalation in

patients with Crohn's disease at a tertiary referral center. Inflamm Bowel Dis 2012;18:10-6.

171. Sandborn,WJ, Feagan BG, Rutgeerts P et al. Vedolizumab as induction and maintenance therapy for Crohn's disease. N Engl J Med 2013;369:711-21.

172. Kansal S, Wagner J, Kirkwood CD, et al. Enteral nutrition in Crohn's disease: an underused therapy. Gastroenterol Res Pract 2013;2013:482108.

173. Lee D, Albenberg L, Compher C, et al. Diet in the pathogenesis and treatment of inflammatory bowel diseases. Gastroenterology 2015;148:1087-106.

174. El-Matary W, Otley A, Critch J, et al. Enteral Feeding Therapy for Maintaining Remission in Crohn's Disease: A Systematic Review. J Parenter Enteral Nutr 2015; Dec 8. pii: 0148607115621051

175. Dickinson RJ, Ashton MG, Axon AT, et al. Controlled trial of intravenous hyperalimentation and total bowel rest as an adjunct to the routine therapy of acute colitis. Gastroenterology 1980;79:1199-204.

176. González-Huix F, Fernández-Bañares F, Esteve-Comas M, et al. Enteral versus parenteral nutrition as adjunct therapy in acute ulcerative colitis. Am J Gastroenterol 1993;88:227-32.

177. Lochs H, Steinhardt HJ, Klaus-Wentz B, et al.Comparison of enteral nutrition and drug treatment in active Crohn's disease. Results of the European Cooperative Crohn's Disease Study. IV. Gastroenterology 1991;101:881-8.

178. Wilschanski M, Sherman P, Pencharz P, et al. Supplementary enteral nutrition maintains remission in paediatric Crohn's disease. Gut 1996;38:543-8.

179. Afzal NA, Davies S, Paintin M, et al. Colonic Crohn's disease in children does not respond well to treatment with enteral nutrition if the ileum is not involved. Dig Dis Sci

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induction of remission in children with Crohn's disease demonstrates that disease phenotype does not influence clinical remission. Aliment Pharmacol Ther 2009;30:501-7.

181. Rubio A, Pigneur B, Garnier-Lengliné H, et al. The efficacy of exclusive nutritional therapy in paediatric Crohn's disease, comparing fractionated oral vs. continuous enteral feeding. Aliment Pharmacol Ther 2011;33:1332-9.

182. de Bie C, Kindermann A, Escher J. Use of exclusive enteral nutrition in paediatric Crohn's disease in the Netherlands. J Crohn's Colitis 2013;7:263-70.

183. Harper PH, Lee EC, Kettlewell MG, et al. Role of the faecal stream in the maintenance of Crohn's colitis. Gut 1985;26:279-84.

184. Harper PH, Truelove SC, Lee EC et al. Split ileostomy and ileocolostomy for Crohn's disease of the colon and ulcerative colitis: a 20 year survey. Gut 1983;24:106-13.

185. Allan A, Andrews H, Hilton CJ, et al. Segmental colonic resection is an appropriate operation for short skip lesions due to Crohn's disease in the colon. World J Surg 1989;13:611-4.

186. Andersson P, Olaison G, Hallböök O, et al. Segmental resection or subtotal colectomy in Crohn's colitis? Dis Colon Rectum 2002;45:47-53.

187. Bernell O, Lapidus A, Hellers G. Recurrence after colectomy in Crohn's colitis. Dis

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Colon Rectum 2001;44:647-54. 188. Martin ST, Vogel JD. Restorative procedures in colonic crohn disease. Clin Colon

Rectal Surg 2013;26:100-5. 189. Kiran RP, Nisar PJ, Church JM, et al.The role of primary surgical procedure in

maintaining intestinal continuity for patients with Crohn's colitis. Ann Surg 2011;253:1130-5.

190. Schwarz RJ, Pezim ME. Failure of right-sided coloanal anastomosis for treatment of left-sided ulcerative colitis. Report of a case. Dis Colon Rectum 1991;34:618-21.

191. Maser EA, Sachar DB, Kruse D, et al. High rates of metachronous colon cancer or dysplasia after segmental resection or subtotal colectomy in Crohn's colitis. Inflamm

Bowel Dis 2013;19:1827-32. 192. Tekkis PP, Heriot AG, Smith O, et al. Long-term outcomes of restorative

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193. Fazio VW, Kiran RP, Remzi FH, et al. Ileal pouch anal anastomosis: analysis of outcome and quality of life in 3707 patients. Ann Surg 2013;257:679-85.

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Authors/ref Country Years analysed

Number of cases all CD

All CD % female

Isolated colonic CD as % of total CD

Isolated colonic CD % female

CD excluding Isolated colonic % female (calculated)

Median Age at presentation (colonic CD)

unspecified or indeterminate as ratio to colonic CD in same series

Cornes10 UK 1961 131 46 34 60 38 41-50 -

Gollop39 USA 1943-82

103 64 36 68 62 25-34 -

Loftus40 USA 1940-93

225 54 32 - - - -

Humphreys41 UK 1966-81

440 58 40 - - - -

Ekbom42 Sweden 1965-83

1469 53 25 - - 33 (mean) -

Kyle35 UK 1955-88

856 63 41 63 63 40-49 -

“ “ “ “ 1964-69

122 - 30 - - - -

“ “ “ “ 1970-75

167 - 40 - - - -

“ “ “ “ 1976-81

204 - 46 - - - -

“ “ “ “ 1982-87

263 - 54 - - - -

Lapidus37 Sweden 1955-59

83 61 14 - - - -

1960-64

145 48 15 - - - -

1965-69

270 51 21 - - - -

1970-74

364 53 26 - - - -

1975-79

331 54 26 - - - -

1980-84

348 58 32 - - - -

1985-89

395 49 32 - - - -

Gunesh36 UK (Cardiff)

1950-60

40 - 13 - - - -

“ “ “ “ 1960-70

89 - 17 - - - -

“ “ “ “ 1970-80

148 - 34 - - - -

“ “ “ “ 1980-90

217 - 38 - - - -

Yapp43 UK (Cardiff) 1991-95

84 68 43 - - - -

Gunesh36 “ “ 1996-2005

212 61 43 68 55 - -

Jayanthi44 UK 1972-89

235 50 25 (incr from

1972 to 89)

- - - -

Cottone45 Italy 1975-95

882 - 18 - - - -

Jacobsen46 Denmark 1978-87

196 67 (1978-

87)

32 - - - -

“ “ “ “ 1988-97

354 “ “ 42 - - - -

“ “ “ “ 1998-2002

230 “ “ 51 - - - -

Wright47 S.Africa 1980-84

134 69 27 - - - 0.44

Manninen48 Finland 1986-99

470 50 40% 1986 31% 1999

- - - 0.56

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Economou49 Greece 1983-2005

105 37 40 - - - 0.40

Rhodes50 UK 1984 395 55 22 72 50 28 (subset)

-

Gower-Rousseau51

France 1994 674 57 19 - - 28 1.15

Auvin52 France 1988-99

367 (< 17y)

47 10 - - - 0.54

Spanish53 Spain 1997 635 52 17 - - - -

Jess54 Denmark 1962-87

374 58 30 - - - -

“ “ “ “ 1991-93

58 66 43 - - - -

“ “ “ “ 2003-04

209 54 37 - - - -

Chow55 China 1987-2005

109 29 35 - - - -

Chouraki38 France 1988-2007

7409 56 11 - - - 0.90

“ “ “ “ 1988-90

544 - 23 - - - -

“ “ “ “ 1997-99

1044 - 13 - - - -

“ “ “ “ 2006-07

533 - 5 - - - -

Romberg-Camps56

Netherlands 1991-2003

476 61 27 66 59 34 (mean) 0.63

Bjornsson57 Iceland 1995-2009

279 54 55 - - - 0.08

Tozun58 Turkey 2001-03

216 44 26 - - - -

Lakatos59 Hungary 2002-06

163 48 36 -

Nguyen60 USA/Canada 2003-05

579 - 19 - - - 0.30

Ott61 Germany 2004-06

168 55 18 - - - 0.43

Siddique62 Kuwait 2005-6 206 52 14 - - - -

Chen63 USA 2005-10

628 55 21 50 56 - -

Lucendo64 Spain 2000-12

599 49 24 - - - 0.10

Henckaerts65 Belg 2007 874 - 17 - - - 0.03

Herrinton66 USA 2008 948 55 40 - - - 0.10

Hancock67 UK 2008 675 62 20 (“enriched”)

74 59 31 (mean) -

Aloi68 Italy 2009-13

10 (<5y)

- 50 - - - -

“ “ “ “ “ “ 215 (6-18y)

- 15 - - - 1.00

Aljebreen69 Saudi 2009-13

497 41 8 - - - -

Burisch70 Western europe

2010 345 48 26 - - - 1.19

“” “” Eastern europe

2010 99 41 20 - - - 0.30

Eglinton71 NZ 2011 507 63 42 - - - -

Ng72 Asia-pacific 2011-12

166 Asia 39% Austr 52%

24 - - - 0.53

Cleynen17 16 countries 2015 16,902 56 24 - - - 0.06

Table 1. Studies of Crohn’s disease age and sex distribution and proportion of total, where isolated colonic Crohn’s disease separately identified (in approximate median date order).

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• “current smoking” variably either smoking at time of diagnosis or at time of sampling but excluding “ex-smoking”

Table 2. Studies of smoking in Crohn’s disease where isolated colonic disease separately identified

Author/ref Year Country Number of cases CD

Nature of study Current smoking OR/RR for CD phenotype

Current smoking * isolated

colonic CD %

Current smoking all

CD%

Current smoking

CD excluding isolated

colonic %

Current smoking healthy

controls %

Current smoking

UC %

Somerville73 1984 UK 82 Case control RR for smoking and CD: Small bowel only 3.5 (0.8-

14.6) Colon only 4.7 (1.4-16.1) Small and large bowel 4.5

(1.8-11.5)

- 56 - 26 -

Holdstock74 1984 UK 150 Consecutive outpatients

- 25 (smokers

with isolated colon CD had more relapses P=0.028)

35 52 - 8

Tobin75 1987 UK 137 Case control RR for smoking at onset and CD:


Ileum and asc colon 6.0 (2.1-17.2)

Small bowel and rest of colon 3.9 (1.5-10.2)

Colon only 2.5 (0.8-7.3)

- 47 - 33 (controls for UC 40%)

11

Lindberg76 1992 Sweden 231 Postal questionnaire

(95% response)

- 42 51 53 - -

Breuer-Katschinski77

1995 Germany 346 Postal questionnaire

(82% response)

- 49 50 49 - -

Russel78 1998 Europe (20

centres, 13

countries)

457 Prospective consecutive

cases

- 35 47 59 - 16

Cosnes79 1999 France 622 Consecutive outpatients

- 54 49 49 - -

Cosnes80 2004 France 688 all colonic

Consecutive outpatients

- 61 - - 42

Aldhous81 2007 UK (Scotland)

408 Retrospective outpatients

- 33 43 50 - -

Hancock67 2008 UK 675 Database OR 1.64 (1.09-2.45) for never smokers with isolated

colonic CD vs ileal or ileocolonic

51 (ever)

61 (ever)

63 - -

Chen82 2011 USA 628 University database

OR 1.69 (1.07-2.66) for any ileal involvement (L1+L3)

vs colon only (L2)

25 37 38 - -

Nunes83 2013 Spain 3224 National registry

- 26 34 35 - -

Chivese84 2015 S. Africa 194 Prospective consecutive

cases

RR 3.63 (1.32-9.98) for ileo-colonic vs colonic;

RR 3.54 (1.06-11.83) for ileal vs colonic

62 73 79 - -

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Author/Ref Study design N (total CD) n/% isolated colonic CD taking

OC at onset

n/% all other CD taking OC at

onset

OR/RR (95%CI) for OC use compared

with healthy controls (when documented by

disease location)

OC use in isolated

colonic vs all other CD

Rhodes50 Case control matched for

age and year of onset

37 9/12 75% 11/25 44% - NS Increased P=0.09

Vessey90 Cohort study in patients

attending family planning clinics

18 4/7 57% 4/11 36% - NS increased 0.63

Lashner91 Case control 51 (incl 8 isolated colonic)

- - Isolated colonic OR0.50(0.05–5.26)

Small bowel only 1.25 (0.34–4.64)

Ileocolonic

0.56(0.20-1.52)

NS reduced (and no

significant association in

this study between OC use and any

Crohns)

Sandler92 Case control Age matched and excluding onset before

menarche


- - Isolated colonic OR2.63 (1.00-7.11)


Ileocolonic 1.52

(0.82-2.83)

NS increased

Persson93 Case control age and sex

matched

152 - - Isolated colonic RR 3.6 (1.1-12.2)

Small bowel only

0.8 (0.3-2.4)

Ileocolonic 1.7 (0.8-4.0)

NS increased

Katschinski94 Case control pre-

menopausal

90 (incl 30 isolated

colonic)

- - Isolated colonic RR3.2 (1.1-15.3)

Small bowel only RR4.7 (1.6-17.8)

Ileocolonic

RR 3.8 (1.3 -17.0)

NS reduced

Khalili95,96 Cohort – Nurses Health


- - Isolated colonic HR4.13 (1.77-9.68)

Ileal only

HR2.99 (1.06-8.49)

NS increased

Table 3 – Studies of oral contraceptive usage in Crohn’s disease where isolated colonic disease separately identified.

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Author/Ref Year Study design N (isolated colonic

CD)

ASCA IgA

(n/%)

ASCA IgG

(n/%)

ASCA (IgG or IgA) (n/%)

pANCA (n/%)

ompC (n/%)

GP2 UC results in same study

Comments

Duerr115 1991 Prospective 18 - - - 5/18 (28%)

- - pANCA 34/40 (85%) pANCA+ in isolated colonic CD not signif commoner than

diarrhea-predom IBS (4/27 15%)

Cambridge116 1992 Stored sera IBD and healthy controls

18 - - - 1/18 (6%)

- - pANCA 27/50 (54%) pANCA+ in 4/32 CD with small bowel involvt

Joossens117 2002 Prospective follow-up of 97 patients with initial

diag of indeterminat

e colitis

17 NA NA 10/17 (59%)

6/17 (35%)

- - ASCA+ in 3/14 (21%) pANCA+ in 8/14 (57%)

All patients initially indeterminate

Lawrance118 2004 Prospective Caucasian

and Chinese

35 6/35 (18%)

9/35 (26%)

NA NA - - ASCA IgA 6/100 ASCA IgG 11/100

ASCA less likely positive in isolated colonic CD than CD

with ileal involvement

Annese119 2004 Prospective 61 NA NA 25/61 (41%)

- - - ASCA 32/197 (16%) ASCA in CD overall 51%

Ferrante120 2007 Prospective study IBD

plus non-IBD and healthy

controls

70 NA 6% NA 21% 3.5% - ASCA IgG 9.6% pANCA 37%

All antimicrobial abs lower titre in isolated colonic CD than

other CD

Vind121 2008 Prospective cohort

60 NA NA 5/60 (8%) 15/60 (25%)

- - ASCA 14% pANCA 55%

ASCA CD overall 22%

Lakatos122 2009 Cohort 143 NA NA NA NA - - ASCA(either IgA or IgG)+/pANCA-

combination in 9% UC

ASCA(either IgA or IgG)+/pANCA- combination in

52% isolated colonic CD

Bogdanos123 2012 Prospective paediatric

32 NA NA 5/32 (16%) - - 2/32 (6.2%)

GP2 9/102 (8.8%) ASCA 7/102 (7%)

GP2 ab (IgG or IgA) in 49/137 (35.8%) other (nonL2) CD

ASCA 55/137 (40.1%) other (nonL2) CD

Bertin124 2013 Prospective recruited at colonoscopy

67 NA NA 21/67 (31%)

- 15/67 (22%)

- ompC 2/35 (6%) ASCA 5/35 (14%)

Colon mucosal culture supernatant ab measures

discriminated better between L2 CD and UC

Elkadri111 2013 Prospective cohort adults and children

55 NA NA NA but OR 0.25 (0.12-

0.51; P=0.0002) for assocn

with isolated colonic

disease vs other sites

NA but OR 2.27 (1.50 – 4.92;

P<0.03 for

assocn with

isolated colonic disease

42.7% all CD,

isolated CD NA

- ASCA (either IgA or IgG) in 12.1% UC;

62.9% CD; pANCA in 55.6% UC,

14.3% CD; anti-OmpC in 28.0%

UC, 42.7% CD

ASCA positivity less common in isolated colonic CD than other

sites

Table 4. Serological test results in isolated colonic Crohn’s disease and ulcerative colitis.

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*Though the study included patients with isolated colonic CD, results were pooled for patients with colonic involvement #Willing 2010, similar patient cohort to Willing (2009) but sequencing methodology compared to terminal-restriction fragment length polymorphism in Willing (2009). ‡FE index was calculated as [log10 (F/Hc) − log

10 (E/Hc)/log10 (TB/Hc), F being the 16S rRNA gene copies of F. prausnitzii, E the 16S rRNA gene copies of

E. coli, Hc a million of human cells, and TB a million of 16S rRNA gene copies of total bacteria.

Table 5: Studies of mucosal microbiota in Crohn’s disease where isolated colonic disease separately identified

Author/ref Year Specimen type

Number of cases

CD

Ileal CD Ileocolonic CD Isolated colonic CD Ulcerative colitis

Healthy controls

Conclusions

Naftali133 2016 Ileum and colon

31 15 Increased abundance

of Escherichia and reduced

Faecalibacterium; disease activity correlated with abundance of Fusobacterium

8* Similar to colonic CD apart from Faecalibacterium abundance 2.7-fold lower than in isolated colonic CD (not significant)

8* Higher levels of

Faecalibacterium and 2 unidentified

genera of the Clostridiales and

Ruminococceaea; lower levels of

Enterobacteriaceae compared with ileal

NA NA Ileal CD and colonic CD microbiomes

distinct

Haberman13

4 2015 Ileal

biopsy 243

(Paediatric)

180 Persistent reduction in Lachnospiraceae,

Bifidobacteriaceae, Clostridiales, and Erysipelotrichaceae in all forms of CD, with

expansion of Veillonellaceae, Pasteurellaceae, Neisseriaceae,

Gemellaceae, Fusobacteriaceae, and Enterobacteriaceae

63 Persistent reduction in Lachnospiraceae, Bifidobacteriaceae, Clostridiales, and

Erysipelotrichaceae in all forms of CD, with expansion of Veillonellaceae, Pasteurellaceae, Neisseriaceae, Gemellaceae,

Fusobacteriaceae, and

Enterobacteriaceae

73 Increased abundance of Firmicutes phyla

43

No difference between

ileal/ileocolonic CD and colonic CD microbiome

Lopez-Siles132

2014 Ileum and colon

45 19 Reduction in F. prausnitzii, E. coli moderately increased.

13 Reduction in F.

prausnitzii

13 F. prausnitzii

comparable to UC; E. coli commoner

than UC particularly in ulcerated zones

28 F. prausnitzii abundance intermediate between CD

and HC.

28 F. prausnitzii/ E. coli (FE index)‡ allowed differentiation

between ileal CD and other CD

phenotypes. Microbiota changes in colonic CD intermediate

between ileal CD and UC.

Willing#130,13

1 2009,2010

Ileum and colon

14 6 Increased Enterobacteriaceae and Ruminococcus gnavus; decreased Faecalibacteria and Roseburia and compared to healthy controls. Increased E. coli.

8 No reduction in

Faecalibacterium or Roseburia. Some increase in E. coli but less marked than ileo-colonic.

6 Colonic CD microbiome intermediate between ileal CD and healthy controls.

Baumgart129 2007 Ileum 29 13 Increased abundance of Enterobacteriaceae, (E. coli, Shigella) reduction in Lachnospiraceae, (Ruminococci, Roseburia and Coprococci) and Clostridiales ( Faecalibacteria and Subdoligranula)

8 Results not presented separately

8 Enterobacteraciae not increased and Faecalibacteria not

reduced.

NA 7

Ileal CD and colonic CD microbiome were distinct. Colonic CD more closely resembled healthy controls

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5ASA Placebo P value Conclusions

Singleton140 64 CDAI mean change: -77 (+/-27) at 2g/day -81 (+/-31) at 4g/day

CDAI mean change -52 (+/-31)

Overall <0.01 for mesalazine vs

placebo in all CD, P=0.42 for

difference in ileal vs ileocolonic vs

colonic

High placebo response rate in isolated colonic CD so NS if this

group taken alone; better response in ileal only disease

(a) Placebo-controlled trials of oral 5-aminosalicylic acid in isolated colonic Crohn’s disease (i) induction


5ASA relapse rate 12months


P value Conclusions

International141 56 32.1% (9/28)

38.9% (11/28)

0.49 5ASA only showed benefit in ileal

disease

Prantera142 18 40% (2/5)

55% (6/?11) extrapolated

from table

NS 5ASA only showed benefit in ileal

disease

Gendre143 48 - - - 5ASA better (P<0.003) than

placebo in all CD patients in remission <3m at onset, no sig difference according to disease location

De Franchis144 36 45% (8/17)(extrapolated

from figure)

45% (9/19)

1.0 5ASA ineffective in ileal, colonic, or

ileocolonic

(a) Placebo-controlled trials of oral 5-aminosalicylic acid in isolated colonic Crohn’s disease (ii) maintenance

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Sulphasalazine remission

Placebo remission

P value Conclusions

Singleton146 20 - - NS Both groups also received tapering

prednisolone. Placebo better

than sulphasalazine in patients with ileal

disease.

Summers147 17 - - 0.006 (comparison of outcome ranks)

Sulphasalazine better than

placebo in colonic CD (also effective in ileocolonic but

not ileal only)

Malchow148 27 31% (4/13)

14% (2/14)

0.4 NS for remission but P<0.01 for

effect when judged by “failure and

relapse”

(b) Placebo-controlled trials of oral sulphasalazine in isolated colonic Crohn’s disease (i) induction


Sulphasalazine relapse rate 12months


P value Conclusions

Singleton146 20 - - NS Sulphasalazine not significantly different from placebo in CD

overall and no relation to disease

location

Summers147 19 - - NS No significant effect (judged by outcome

rank based on CDAI)

(b) Placebo-controlled trials of oral sulphasalazine in isolated colonic Crohn’s disease (ii) maintenance

Author/Ref N (Isolated colonic CD)

Olsalazine relapse /failure rate 12

months

Placebo relapse /failure rate 12

months

P value Comments

Mahmud145 145 65.4% 53.6% 0.035 (Olsalazine worse)

Olsalazine induces diarrhea, no

evidence of efficacy

(c) Placebo-controlled trial of olsalazine in isolated colonic Crohn’s maintenance

Table 6. Trials of 5ASA preparations where data presented separately for isolated colonic Crohn’s disease.

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Rifaximin remission rate

Placebo remission rate

P value Conclusions

Prantera152 190 active; 76 placebo

(from supplement

table 2)

Placebo Week 12 remission

(CDAI <150)

3 doses: 400mg bd; 800 mg bd; 1200 mg bd; no dose

response overall; pooled doses

remission in 96/190 (51%)

28/76 (37%) 0.04 Rifaximin more effective for colonic than ileal disease

(a) Controlled trial of oral rifaximin


CD)


Metronidazole response rate

Placebo response rate

P value Conclusions

Blichfeldt153 6 Placebo (crossover)

Week 8 response

100% ? NS overall Metronidazole 1g daily

improved symptoms

and lab values in all

six with colonic disease

Sutherland154 12 (4 received 10 mg/kg; 4 received 20mg/kg; placebo)

Placebo Week 16 response

Mean CDAI drop 145, 95% CI 26-

265, n=8

CDAI increased by mean of 61,

n=4

0.05 Metronidazole more effective than placebo in colonic and

ileocolonic disease but not small

bowel disease

(b) Controlled trials of oral metronidazole

Table 7. Trials of antibiotics where data provided separately for patients with isolated colonic Crohn’s disease.

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CD)

Budesonide/ Comparator

Primary end point

Budesonide remission

rate

Comparator remission

rate

P value

Steroid related adverse events

Conclusions

Tromm157 50 (distal colon

excluding rectum) of 307 in

trial

Budesonide 9mg od vs 3mg tds vs

Mesalamine 1.5g tds


23/30 (76.7%)

10/20 (50%)

0.051 Only 1 budesonide patient with acne, no other steroid-related events

Budesonide borderline signif

better than mesalamine

Bar-Meir158 27 of 201 in trial

Budesonide 9mg od vs Prednisone

40mg od 2wks then

taper


2/10 (20%) 10/17 (58.8%)

0.1 67% Prednisone vs 44% Budesonide

Trend towards better efficacy in colonic disease with Prednisone, similar efficacy if

small bowel involved.

(a) Controlled trials of pH-modified release oral Budesonide


CD)

Prednisone/Comparator Primary end point

Prednis(ol)one remission

rate

Comparator remission rate

P value Conclusions

Summers146 34 of 295 in trial (Pt1)

Prednisone up to 60mg /day (n=8) vs

Azathioprine 2.5 mg/kg (n=9) vs

Sulfasalazine 1g/15kg (n=8) vs

Placebo (n=9)

Week 17 remission



0.465 Prednisone not effective

in colon only

disease (but only

n=8 treated)

Malchow147 49 of 215 in trial

(induction data from

table 11)

Sulfasalazine or combination of

sulfasalazine and 6-methyl Prednisolone

Remission by week

18

6/8 (75%) Placebo 2/14 (14%)

Sulphasalazine 4/13 (31%) Combination 13/14 (93%)

<0.01 for Sulfasalazine and

6-methylprednisolone and <0.001 for

combination

All active treatments better than placebo but combination superior to

either agent alone

(b) Controlled trials of oral Prednis(ol)one Table 8. Trials of oral corticosteroids where data provided separately for isolated colonic Crohn’s disease.

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Author Year Type of study

Study agent Total number of patients

Number with

colonic CD

Endpoint Main findings P value (for

colonic vs other sites

unless stated)

Conclusion

Sandborn165 2011 RCT Certolizumab pegol (CZP)

338 120 Week 6 remission (CDAI </=150)

23/63 (36.5%) CZP vs 10/57

(17.5%) placebo

0.052 (colon vs

other locations);

0.034* (active vs placebo)

Probable efficacy in

colonic disease

Arnott166 2003 Cohort Infliximab 74 26 Week 4 response (fall in HBI by >3)

23/26 (88%) response in colonic vs 6/11 (54%) in ileal


colonic than ileal

Laharie167 2005 Cohort Infliximab 44 18 Week 8 response (fall in CDAI by >/= 100)

83.3% colonic CD vs 50% ileal/ileocolonic



ileal/ileocolonic

Vermeire168 2002 Cohort Infliximab 240 89 Week 4 (luminal) or week 10 (fistulising) response (fall in CDAI by >/=70 or 50% decrease in draining fistulae

81% response colonic CD vs 55% ileal CD vs 74% ileocolonic OR 1.905, 95% CI 1.010 – 3.597



ileal/ileocolonic.

Remission also more likely in isolated colonic

(P=0.019)

Dupont-Lucas169

2016 Cohort

Infliximab 248 (children)

63 Loss of response to maintenance therapy (moderate or severe global assessment requiring cessation of therapy)

Colonic 25/54 (46%) responders or remitters vs ileal/ileocolonic 148/185 (80%). iHR 2.72 (95% CI 1.30-5.71) for loss of response in isolated colonic CD vs other sites

0.008 Isolated colonic disease

more likely to lose

response

Cohen170 2012 Cohort Adalimumab 75 15 Time to dose escalation

13.2 weeks for colonic vs 34.6 weeks for other sites

0.0062 Isolated colonic disease required

earlier dose escalation

Sandborn 171 2013 RCT Vedolizumab 1115 316 (273 active, 43 placebo) Subgroup analysis based on 62 active and 43

placebo.

Remission (CDAI </=150) at week 6 over placebo, Response (CDAI fall >/=100) week 6

Remission difference from placebo: 5.9% for colonic vs 6.7% for ileal vs 8.9% for ileocolonic Response: 10.6% for colonic vs minus 10.4% for ileal vs 7.1% for ileocolonic

0.30 remission

0.23 response


colonic and other

Crohn’s for induction

with vedolizumab

Sandborn171 2013 RCT Vedolizumab 461 117 Remission at week 52 over placebo

Remission 8wkly vedo: 18.9% difference from placebo for colonic vs 11.8% for ileal

0.11

0.19


colonic and other

Crohn’s for

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vs 19.9% for ileocolonic Remission 4wkly vedo: 12.7% for colonic vs 25.4% for ileal vs 12% for ileocolonic

maintenancewith

vedolizumab

Table 9: Randomized controlled trials (RCTs) and cohort studies of biological therapy in

Crohn’s disease where data were provided separately for patients with isolated colonic

disease.

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Author/ref Year Nature of

study

Adults/ children

n= Intervention Duration Primary endpoint

Results in patients with ileal

involvement

Results in isolated

colonic CD

P*

Lochs177 1991 RCT Adults 55 (enteral nutrition; 9 colon only);

52 drug treatment

Exclusive Peptisorb

(oligopeptide diet)

4-6 weeks

Remission (CDAI

reduced by 40% or 100

points)

Mean time till

remission 26 days

Mean time till

remission 31 days

NS

Wilschanski178 1996 Retrospective cohort

Children 7-17

65 (5 colon only)

Exclusive Amino-acid or peptide

4weeks or more

Remission PCDAI </=20


Remission 1/5 (20%)

0.02

Afzal179 2005 Prospective

cohort

Children 8-17

65 (14 colon

only)

Exclusive polymeric

8weeks Remission PCDAI<20



0.01

Buchanan180 2009 Prospective

cohort


110 (19 colon only)


in 105, elemental

in 5

8 weeks Remission (improvt in all domains

of global assesst)

Remission 73/91

(80.2%)

Remission 15/19

(78.9%)

NS

Rubio181 2011 Retrospective cohort

Children Mean age

11

106 (26 colon only)


8 weeks Remission PCDAI<10

Remission 86/106 (81%) overall, colonic data not presented separately but site not correlated with

outcome

NS

De Bie182 2013 Retrospective cohort


76 (18 colon only)

Exclusive polymeric or semi-

polymeric

6 weeks Remission defined as

no diarrhea, pain or wt

loss



NS

Table 10. Results of exclusive enteral nutrition as primary therapy in Crohn’s disease where data provided separately for isolated colonic Crohn’s disease.

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Ileal/Ileocolonic

Crohn’s disease

Isolated colonic

Crohn’s disease

Ulcerative colitis

Sex Slightly commoner in females (c55%)

Commoner in females (c65%)

Equal or slight male predominance

Genetics Crohn’s-associated genotype including

NOD2/CARD15

Genotype midway between Crohn’s and

UC Associated with HLA-DRB1*01:03 but not

NOD2/CARD15

UC-associated genotype including HLA-DRB1*01:03

Smoking Marked association Worsens prognosis

Weak association Possibly worsens

prognosis

Marked negative association

Oral contraception Positively associated Positively associated Positively associated (mainly in smokers)

Serology ASCA commonly positive

pANCA usually negative

ASCA less commonly positive than

ileal/ileolonic CD pANCA positive in

minority

ASCA usually negative pANCA commonly

positive

Mucosa-associated Microbiota

Marked changes commonly including

increased Proteobacteria (eg E.

coli) and Fusobacteria, reduced Firmicutes (eg

F. prausnitzii

Intermediate changes similar to ileal/ileo-colonic CD but less

consistent

Modest changes, including slight

increase in E. coli but no reduction in F.

prausnitzii

Response to mesalazine

No efficacy No efficacy Good efficacy

Response to anti-TNF Good efficacy Good efficacy – probably better than for ileal/ileocolonic

Good efficacy

Response to excusive enteral nutrition

Good efficacy Probably good efficacy but mixed reports

No efficacy

Surgery rate and type

Required in majority Required in minority Segmental colectomy

effective High failure for pouch-

anal reconstruction

Required in minority Segmental colectomy

not effective Low failure for pouch-

anal reconstruction

Table 11. A summary of the distinguishing features of the three inflammatory bowel diseases: ileal/ileocolonic Crohn’s disease, isolated colonic Crohn’s disease, ulcerative colitis.

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Documents

Confidential: For Review Only · The genetics of isolated colonic Crohn’s disease place it approximately midway between Crohn’s disease with small intestinal involvement and ulcerative